DD148334A5 - PROCESS FOR PREPARING SUBSTITUTED CYCLOHEXANDIONES (1.3) - Google Patents

Abstract

The invention relates to a process for the preparation of a compound of the formula V in which R is a phenol protecting group, 2 alkylene having 1 to 13 carbon atoms or - (alk & ind1!) M -O (alk & ind2) n, where (alk & ind1!) And (alk & ind2! ) Alkylene of 1 to 13 carbon atoms, provided that the sum of the carbon atoms of (alk & ind1!) And (alk & ind2!) Is not greater than 13 and where n and m are 0 or 1 and where W is hydrogen, pyridyl or the group with W & ind1! = Hydrogen, fluorine or bromine. The compounds prepared according to the invention are valuable intermediates for the preparation of 3- & 2-hydroxy-4- (substituted) phenyl! Cycloalkanones and -cycloalkanols. These compounds can be used as (NS agents, especially as analgesics, tranquilizers, sedatives and antianxialytics ,

Description

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Manufacturing process for intermediates for Representation of 3 - / ^ - hydroxy - 4 ~ (sub statuierten)

and cycloalkanols

Field of application of the invention ;

The invention relates to a process for the preparation of compounds of general formula (V),

ο α

z-w

valuable intermediates for the production of 3 - / ^ - hydroxy ⁱ f- (substituted) phenyl.7cycloalkanon- and eyeloalkanol agents represent .. In the formula (V): Q: a Phenolschutsgruppe

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Z is alkylene having 1 to 13 carbon atoms, or - (all,) -O- (aiko) "-, wherein alK ₁ and alk _{9 are} alkylene having 1 to 13 carbon, provided that the sum of the carbon atoms in (alkxj) , plus (alkg) is not greater than 13 and η and m is 0 or 1,

W: hydrogen, pyridyl or: V / ^, wherein W ^ is hydrogen, fluorine or chlorine.

The preparation of the above-mentioned cycloalkanones and cycloalkanols and the unsaturated analogs thereof having 5 to 8 carbon atoms in the cycloalkyl ring using the aforementioned intermediates is described in a priority application of the same. The end-products are useful as (NS agents, especially as analgesics, tranquilizers, sedatives and antianxial agents in mammals, including humans, or as anticonvulsants, vulsiva, dinretics and antidarrhoika in mammals, including humans.

C ha rakteristi k of the known technical solutions:

Although a number of analgesic agents are currently available, the case continues to look for new and improved remedies, suggesting the lack of an agent suitable for the treatment of a variety of pain with a minimum of side effects. The most widely used agent Aspirin is virtually ineffective in relieving severe pain and is known to cause various undesirable side effects. Other analgesic agents, such as d-propoxyphene, codeine and morphine lead to addiction. The development of improved and potent analgesic agents is therefore necessary.

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US Pat. No. 3,576,887, issued April 27, 1971, discloses a heine of 1- (1'-hydroxy) alkyl-2-b-hydroxyphenylcyclohexane or compounds which are useful as intermediates for the preparation of 6,6-dialkyltetrahydro- and -hexahydrodiben-zo / F, d7-pyrans, which are useful as passivating agents for the central nervous system.

Explanation of the essence of the invention

It has now been found that certain cycloalkanones, cycloalkanols and unsaturated analogs thereof which have a 2-hydroxy-4- (substituted) phenyl group at the 3-position (formula I below) are effective as CNS agents in particular as analgesics, tranquilizers, sedatives and antianxial agents in mammals, including humans, and / or as anticonvulsants, diuretics and antidiarrheals in mammals, including humans. Also included in the invention are various derivatives of these compounds which are useful in dosage forms of the compounds, intermediates for compounds of formula I and methods for their preparation. The compounds have the formula

in which R is selected from the group comprising saturated and unsaturated cycloalkyl components selected from the following group:

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I - A (A, B, taken individually) II - A (A, B taken together)

-Β

I-B

I - Ο (Α, Β taken individually) II - C (A, B taken together) II-D wherein the dashed lines represent an optical double bond at one of the positions, in which case IU can not be present;

A, when taken alone, represents hydrogen;

B, when taken alone, is selected from the group consisting of hydroxy, hydroxyethyl and alkanoyloxy of 1 to 5 carbon atoms (Formula I of the group of compounds);

Sii.

A and B when taken together (Formula II of the group of compounds) are selected from the group consisting of oxo, methylene and alkylenedioxy having from 2 to 4 carbon atoms;

R 1 is selected from the group consisting of hydrogen, alkanoyl of 1 to 5 carbon atoms, benzyl, -P (O) (OH) p and the mono- and disodium and potassium salts thereof, -CO (OIIo) OGOOH and the sodium and potassium salts thereof,

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and -GO- (OHO) ₀ -NRcHg wherein ρ is an integer from 1 to 4; Rr and Εξ, when taken individually, are each selected from the group consisting of hydrogen and alkyl of 1 to 4 carbon atoms; He and R ^, when together with the nitrogen to which they are attached, form a 5- or 6-membered heterocyclic ring of the piperidino, pyrolo, pyrrolidino, morpholino and N-alkylpiperazino having 1 to 4 carbon atoms in the alkyl group include the group selected;

R 'is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 3 to 6 carbon atoms, phenyl and phenylalkyl. Is selected from 1 to 4 carbon atoms in the alkyl group;

R-2 is selected from the group consisting of hydrogen and methyl;

R 1 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, provided that R _{2 is} hydrogen when R 1 is methyl;

Z is selected from the group consisting of (a) alkylene of 1 to 13 carbon atoms (b) -O- (alkp) wherein

each (alk ^ j) and (alkp) alkylene of 1 to 13 carbon atoms is provided that the sum of the carbon atoms in (alk ^) plus (alk ₂ ) is not greater than 13; m and η each = O or 1; and

W is selected from the group consisting of hydrogen, pyridyl, - ^ D / ^τ ^, wherein W ^ is selected from the group consisting of hydrogen, fluorine and chlorine. ,

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The dashed lines in the compounds of the forms 1 I i. Formulas IA - ID represent the optical presence of a double bond at one of these sites.

Also included in the invention are the pharmaceutically acceptable acid addition salts of those compounds of formula I which contain a basic group. Typical representatives of such compounds are those in which W variable is pyridyl and / or OR 1 is a basic ester component. In compounds in which two basic groups are present, of course, polyacid addition salts are possible. Representative of such pharmaceutically acceptable acid addition salts are mineral acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate, organic acid salts such as citrate, acetate, sulfosalicylate, tartrate, glycolate, malate, malonate, maleate, pamoate, salicylate, stearate, phthalate, succinate, gluconate , 2-Hydroxy-3-napb.tb.eat, lactate, mandelate and methanesulfonate.

Compounds of formula IA-ID, wherein A and B, when taken together, are oxo and IL · is hydrogen, are in solution in equilibrium with their hemiketal forms. The ketone and hemiketal forms of the compounds of formula I are included in the invention ..

Compounds of formula IA-ID wherein A is hydrogen and B are hydroxy contain asymmetric centers on the 1-, the

3- and 4-positions, and where the cycloalkyl group is 6 to 8-membered, at the 5-position in the cycloalkyl component, and may of course contain additional asymmetric centers in the

4- and 5-position substituents and in (-Z-W-) of the phenyl ring. The cis relationship between the substituent

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at the 1-position of the cycloalkyl moiety and the phenol or substituted phenol moiety at the 3-position is preferred, and the trans relationship between the 3- and 4-substituents and the 4- and 5-substituents on the cycloalkyl moiety is preferred, because it has the stronger (quantitative) biological activity. For the same reason, the trans-3> 4 relationship in compounds of formula IA-ID wherein A and B, taken together, are oxo, is also preferred.

For simplicity, the above formulas show the racemic compounds. However, the above formulas are and will be considered to be typical of the racemic modifications of the compounds of the invention, the diastereous mixtures, the pure enantiomers and the diastereomers thereof. The utility of the racemic mixture, the diastereomeric mixture, as well as the pure enantiomers and diastereomers, is determined by the biological evaluation methods described below.

Various intermediates useful in the preparation of compounds of formula I are described in more detail in a priority application. The intermediates have the following formulas II-IV:

(cis and trans isomers)

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(in which no stereochemistry is present).

wherein Z, W, Rp and R-s are as defined above; Y is selected from the group consisting of cyano and formyl; t is a number lying between 1 and 8; Rn is hydrogen and alkyl of 1 to 4 carbon atoms

comprehensive group is selected; and

Q from the -CH ₂ -, -CH ₂ -CH (R ₄ ) -, CH ₂ -CH ₂ -CHCR ₄ ) - and -CH ₂ -CH ₂ -

CH ₂ -CH- (R ₄ ) - comprehensive group is selected.

The compounds of the formula IV are representatives of the hemiketal and ketal forms of the saturated cycloalkyl compounds of the formula I (A-D) in which A and B taken together are oxo.

Because of their greater biological activity compared to the other compounds described herein, compounds of formula IA-ID wherein A and B together are oxo are preferred; A and B, when taken individually, are hydrogen, hydroxy, R _{2 is} hydrogen or alkyl, R _{1 is} hydrogen or alkanoyl, R _{1 is} hydrogen or ethyl; R _{4 is} hydrogen or alkyl; and Z and W have the meanings given below:

Alkylene having 8 to 11 carbon atoms

Alkylene of 4 to 7 carbon atoms

CaIk ₁ ) _m -O- (alk ₂ ) _n ) _m ~ 0-CAlk ₂ ) _n

O O

1 1

W ₁ , pyridyl

W ₁ , pyridyl

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Preferred compounds of the formula I, and especially the saturated cycloalkyl compounds of the formula I, are the favorable compounds in which: R 1 and R 2 are each hydrogen; Z = -G (CH ₃ ) ₂ (CH ₂ ) ₆ and W = hydrogen; Z ss C ^ r ₇ - alkyl en. and W = phenyl; '. Z = -ÖtAlkylen with 7 to 9 carbon atoms and W = hydrogen;

Z =: -O-alkylene having 4 to 5 carbon atoms and W = phenyl; A = hydrogen and B = hydroxy (cis and trans forms); A and "B taken together are oxo; R ₂ = hydrogen, methyl, propyl or propenyl; R 1 = hydrogen or methyl R 1 - hydrogen.

Particular preference is given to the saturated cycloalkyl compounds of the formulas IB and IG, in which R 1, R ₂ , R 1, E ₁ , Z and W correspond to the definition given in the preferred compounds and A and B taken individually represent hydrogen or hydroxy.

Also in terms of analgesic activity, a particularly preferred group of compounds are those preferred compounds listed above in which R _{2 is} methyl, propyl or propenyl and R 1 and R 1 are each hydrogen. ,

The saturated cycloalkyl compounds of formula I wherein E, is hydrogen, are prepared from the corresponding 2-bromo-.5- (ZW-substituted) phenol by a series of reactions comprising, as a first step, the protection of the phenolic group. manufactured. Suitable protection

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pen are those which do not interfere with the subsequent reactions and which can be removed under conditions which do not cause undesirable reactions elsewhere in the compounds or products produced therefrom. Representative of such protecting groups are diethyl, ethyl, benzyl or substituted benzyl in which the substituent is, for example, alkyl of 1 to 4 carbon atoms, halogen (Gl, Br, P, J) and alkoxy of 1 to 4 carbon atoms. The ether protecting or blocking groups can be removed by the use of hydrobromic acid in acetic acid or 48% aqueous hydrobromic acid. The reaction is carried out at elevated temperatures and preferably at the reflux temperature. However, if Z = - (allCi) 0- (alko) _n , acids such as polyphosphoric acid or trifluoroacetic acid must be used to prevent the cleavage of the other ether bond. Other reactants, such as hydriodic acid, pyridine hydrochloride or hydrobromide, can be used to remove ether protecting groups such as methyl or ethyl. "" When the protecting groups are benzyl or substituted benzyl groups, they can be removed by catalytic hydrogenolysis Suitable catalysts are palladium or platinum, especially on carbon support Alternatively, they can be removed by solvolysis using trifluoroacetic acid Another procedure consists in a treatment with n-butyllithium in a reaction-inert solvent at room temperature.

The exact chemical structure of the protecting group is not critical to the invention, as its importance lies in its ability to act as described above. The selection and identification of the appropriate protecting groups can be from a

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Professional easy and fast. The suitability and effectiveness of a group as hydroxy protecting group is determined by the fact that such a group is used in the reaction sequence described here. It should therefore be a group that can be easily removed for the regeneration of the hydroxy groups. Methyl and benzyl are preferred protecting groups as they are easy to remove.

When Rp is an alkenyl group, the cycloalkanones thus produced serve as intermediates for the preparation of the corresponding cycloalkanones (IA-ID) in which the cycloallcano! Compounds of formula I are prepared from the protected cycloalkanones by reduction. In this step, sodium hydride is preferred because it not only gives satisfactory yields of the intended product but also maintains the protecting group on the phenolic hydroxy group and so slowly reacts with hydroxyl solvents (methanol, ethanol, y / acid) that their use as solvents is possible. It is generally applied between about -40 ⁰ C and 3O ⁰ C temperatures. Lower temperatures, even up to about -7O ⁰ C, can be used to increase the selectivity of the reduction. Higher temperatures produce a reaction of the sodium borohydride with the hydroxyl solvent. If higher temperatures appear appropriate or are required for a particular reduction, solvents of isopropyl alcohol or the dimethyl ether of diethylene glycol are used. Slightly, potassium tri-sec-butyl borohydride is preferred as the reducing agent because it promotes stereoselective formation of the trans-1,3-phenylcycloalcohol. The reduction was carried out in dry tetrahydrofuran at a temperature below -5O ⁰ C, to which äqüimolare amounts of the ketone compound and the reducing agent are used. ,

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Reducing agents such as Lithiuiaborhydrid, diisobutylaluminum hydride or Lithiumaluminiuinliydrid, which may also be used, which are not hydroxyls, such as 1,2-dimethoxyethane, tetrahydrofuran, diethyl ether, dimethyl ether of Ithylenglycol.

The cycloalkanols of formula I in which A is hydrogen and B and OR are each hydroxy can, of course, be obtained directly by catalytic reduction of the protected cycloalkanones via palladium-on-charcoal or by catalytic reduction or chemical reduction of the unprotected cycloalkanones (Formula I, A + B = oxo, ORxJ = OH) can be obtained using the reducing agents described above.

In practice, it prefers the unprotected Cycloalkanole of formula I (A = H, B + OR ^ = OH) via the reduction of bezylgeschützten cycloalkanones (formula I, A + B = oxo, 0R ^ = benzyloxy) as described above because it allows the stereochemical control of the reaction and the formation of the cis-hydroxyepimer as the major product, thus facilitating the separation and purification of epimer alcohols. Compounds of formula IB in which the cycloalkyl moiety is saturated and wherein R ₁ other than hydrogen are protected by reacting the corresponding Z-bromo-5- (ZW-substituted) phenyl in which the phenol group is appropriately protected as described above is prepared with magnesium to form the Grignard reagent as previously described. The obtained Grignard reagent is then treated, without isolation, at a reduced temperature about +10 ⁰ C and -20 ⁰ C, treated with N, N- dimethylformamide. The reaction mixture is then allowed to warm to room temperature and the product, a protected 2-hydroxy-4- (ZW-substituted benzaldehyde, is recovered by known methods

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is then converted via the Wittig reaction with the corresponding 1-Triphenylphosphoranyliden ~ 2-alkanone in an inert solvent at a temperature ranging from about room temperature to the reflux temperature of the solvent in a - (2-hydroxy-4- (ZW-substituted) phenyl) Converted to 3-alkenone. By the above 2-propanone derivative, the formation of the cyclohexyl component is possible. The aryl alkenone thus produced is then reacted with a dialkyl malonate, preferably one in which the alkyl groups have from 1 to 4 carbon atoms, to cyclize the alkenone. The reaction erfilgt in an inert solvent such as an alcohol having 1 to 4 carbon atoms at a temperature of about 2 ^ O ⁰ to, reflux temperature of the solvent.

The carbalkoxy-substituted cycloalkane dione compound produced is then removed by treatment with aqueous sodium or potassium hydroxide at elevated temperature, ie, between about 50 and 10O ^{0 0} O G, decarboxylated, and the cycloalkanedione derivative is isolated by conventional methods. Thereafter, the reaction is ketalized with methanol or another alcohol having up to 4 carbon atoms or an alkylene glycol having 2 to 4 carbon atoms in the presence of a dehydrating acid such as p-toluenesulfonic acid.

In the case of the. Cyclonexylderivats the 3-methoxy-2-cyclohexen-1-one derivative is then worked up with lithium aluminum hydride in an inert solvent such as diethyl ether, dioxane, tetrahydrofuran or diglyme in a dilute mineral acid. The resulting aryl-substituted 2-cyclohexan-1-ones are then reacted with the corresponding dialkyl copper lithium in a suitable reaction-free solution.

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tel such as hexane, diethyl ether or mixtures of these solvents or in cyclic ethers such as tetrahydrofuran at a temperature between about O ⁰ O and about -20 ⁰ G temperature treated. The protected 3- / Ji- (Z-t) -supert- [xlerte-2-hydroxyphenyl7 - ^ - R / i-cycloalkanone is then deprotected and reduced or reduced according to the procedures described above and then deprotected.

On the other hand, by reacting 5- / 2 "-benzyloxy-4- (Z-WJ7-3-alkoxy-2-cyclohexen-1-ones with the appropriate Grignard reagent RJAgBr and subsequent acid hydrolysis, the corresponding 5- _i / - form ^{: :.} · 2-benzyl oxy-4- (ZW) phen5 ⁷ · _l7-3-rZl-2-cyclohexen-1-one, which are then subsequently reduced catalytically to the corresponding cyclohexanones the debenzylation as described above, yields the 5- / 2-hydroxy-4- (Z- ^; O-phenyl-3-R, cyclohexanones, which are then reduced as described above to the corresponding cyclohexanols.

Compounds of formula 1-0 wherein the cycloalkyl component is saturated and where R 1 is other than hydrogen are prepared by ring expansion of the cyclohexyl derivative. By reacting the corresponding 5 - / <2-3-benzyloxy-4- (Z-) \ 7) -phenyl7-3-R /, - cyclohexanone with lithium dibromomethane in an inert solvent such as Dieäthyläthern arises 1-

Further reaction of the 1-Dibronunethylcyclohexariols in an inert solvent such as tetrahydrofuran with n B utyllithium gives 3- / 2-IIydr oxy-4- (ZW) -phenyl / 5-R ^ -Cyc1o heptanone, which then according to the previously described Procedures deprotected and reduced or reduced and removed from protection.

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Compounds of formula I-D, vs / in which the cycloalkyl moiety is saturated and wherein R 1 is other than hydrogen, are prepared by ring extension of the cycloheptyl derivative by procedures previously described.

When R 1 in structure IA-IC is hydrogen, then it is possible, according to the procedures previously described, to ring-expand these structures to the methylene-larger ring, i. to IB-ID, to bring about.

The 2-bromo-5- (ZW-substituted) phenol reactants are prepared by bromination of the corresponding 3- (2-V / substituted) phenol by standard methods such as by treatment with bromine in carbon tetrachloride at between 20 and 30 ^° C temperature produced. The necessary 3- (ZW-substituted) phenols are, if they are unknown compounds, obtained by the method explained here. A convenient method for the preparation of reactants in which the Z-component is alkylene or (all,) -O-CaCl-) - is the Wittig reaction of a corresponding aldehyde such as (3-hydroxyphenyl) -2-methylpropionaldehyde , whose hydroxy group is protected by benzyl ether bond. This aldehyde is then treated with the corresponding alkyltriphenylphosphonium trihydrate whose alkyl group extends the propionaldehyde group to the desired length. In a typical procedure the aldehyde reactant to a slurry of Watriuiridimsyl and Alkyltriphenylphosphoniumbromid in DimethyIsulfoxid at below 30 ⁰ C lying temperature, for example 10 to 30 ⁰ C, is added. When the reaction is complete, the alkene-substituted protected phenol is recovered by known methods. The hydrogenation of the alkene over palladium

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Charcoal then gives the intended 3- (Z-W) -substituted) phenol benzyl ether. By carefully selecting the starting (3-hydroxyphenyl) substituted aldehyde and alkyltriphenylphosphonium dibromide reactants, the intended 3- (Z-W-substituted) phenol reactants are recovered.

The preparation of the corresponding 4-Rp-2-cycloalkene-i-one allows the synthesis of the structures of formulas IA-ID, wherein R 1 is hydrogen, according to the procedures described above. The reaction of the corresponding 1,3-cycloalkanedione with an alcohol 1 to 4 carbon atoms and an acid catalyst such as p-toolesulfonic acid in an inert solvent such as benzene or toluene and in an apparatus for the separation of water at temperatures at which the reaction solvent flows back, gives 3-A1-koxy-2-cycloalkene-i-one. By reaction of the corresponding 3-alkoxy-2-cycloalkene-1-one with lithium diisopropylamide in an inert solvent such as tetrahydrofuran in the presence of hexamethylphosphoramide and the corresponding R2X wherein bromide or iodide or other suitable group is present, 4-Rp- Alkoxy ~ 2-cycloalkene-1-one won. Such as diethyl ether at between about -10 and ⁰ 1O G lying temperatures, the 4-R2-3-alkoxy-2-cycloalkene-1-one followed by Lithiumaluminiumnydrid in an inert solvent and reacted filled with dilute mineral acid. The resulting 4-Rp-2-cycloalkene-1-one is then converted using the procedure already described.

Compounds of formula IB-ID wherein the cycloalkyl moiety is saturated and Rp and R are each other than hydrogen are prepared by reacting the appropriate 5- / 2 "-benzyl-

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oxy-4- (ZW) phenyl.7-3-iaethoxy-2-cyclohexen-1-one with lithium diisopropylamide in an inert solvent at a low temperature, for example -50 to - 8 ° 0 produced. Hexane methylphosphoramide and the corresponding Rp iodide (where R _{2 is} not hydrogen) are then added to give a 5- / 2-benzyloxy-4- (ZW) phenyl-7-3-methoxy-6-Rp cyclone. to generate xen-1-on. Further reaction of the compound with the appropriate Grignard reagent R ¹ MgX (wherein R ^{1 is} alkyl) under the usual Grignard reaction conditions

Debenzylation and reduction of the compound according to the procedures described above yields the intended 3- / 2-RJ droxy-4- (ZW) pheny37 ^r -4-R ^ ip-R / j. ¹ -cyclohexanol. By reduction of the double bond of the 3- ^ 2-benzyloxy-4- (Z-7 /) phenyl7 ~ 4 - R ₂ -5-R-cyclohexene-i-one over Pd / C, the corresponding saturated cyclohexanone derivative is obtained. These latter derivatives serve as intermediates for the preparation of the corresponding cycloheptanone and oyclooctanone derivatives by the ring expansion method described above.

A convenient procedure that allows the selective alkylation of 3- (2,4-dihydroxyphenyl) -cycloalkanones at the 4-hydroxy group involves, as a first step, the conversion of 3- (2,4-dihydroxy-phenyl) -cycloalkanone to a ketal. The conversion is carried out according to the generally known methods used for ketalization, such as reaction of 3- (2,4-dihydroxyphenyl) cycloalkanone with an alcohol, especially an alcohol of one to four carbon atoms, in the presence of an acid such as sulfuric acid, p-toluenesulfonic acid, Hydrogen chloride, under conditions that remove the by-product water. A preferred method is the reaction of 3- (2,4-dihydroxyphenyl) cycloalkanol

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with an orthoformate in solution in an alcohol corresponding to the alcohol component of the orthoformate. Trimefcyl orthoforiniate and methanol are preferred reactants in conjunction with concentrated sulfuric acid, anhydrous hydrogen chloride or ammonium chloride catalyst. , ,

The substitution of a methyl or alkyl group at other sites, for example, the beta-carbon atom of the alkylene group is carried out by the choice of the appropriate oarbοalkoxyalkylidentriphenylphosphorans, for example (O ₆ Hc) ₃ P = C (R ¹ ) -C00G ₂ Hc. The resulting unsaturated ester is reduced to the corresponding alcohol by reaction with lithium aluminum hydride. On the other hand, when the phenol protecting group is not benzyl (eg, methyl), the alcohol is produced by catalytic reduction of the unsaturated ester using palladium-carbon monoxide, followed by treatment of the resulting saturated ester with lithium aluminum-minium hydride. Conversion of the resulting alcohol to the corresponding tosylate or mesylate followed by alkylation of the tosylate or mesylate with an alkali metal salt of the appropriate HO.alpha. (Alko) -W reactant and finally deprotection yields the intended 3- (ZW substituted) phenol.

Deviation from the above order provides for the bromination of the alcohol rather than its conversion to a tosylate or mesylate. Phosphorus tribromide is a convenient brominating agent. The bromo derivative is then reacted with the appropriate HO-ialkg)-in in the presence of a suitable base (Y / iliamson-ether synthesis).

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The bromine compounds also serve as valuable intermediates for extending the chain length of the alkylene moiety in the above order to obtain compounds wherein Z is -alkylene-W-. It is known to treat the bromo derivative with triphenyl phosphine to produce the corresponding triphenyl phosphonium bromide , Reaction of the triphenyl phosphonium bromide with the appropriate aldehyde or retone in the presence of a base such as sodium hydride or n-butyl lithium gives an unsaturated derivative which is then catalytically hydrogenated to the corresponding saturated compound.

Another method for introducing an alkyl or aralkyl group into the aromatic nucleus, and especially such a group in which the carbon atom adjacent to the aromatic nucleus is a tertiary carbon atom, is the acid-catalyzed electrophilic aromatic substitution of guaiacol by a tertiary alcohol in the presence of an acid, eg methanesulfonic acid. The general procedure is the reaction of a mixture of methanesulfonic acid and equimolar amounts of guaiacol and tertiary alcohol at between about 30 ⁰ C and about 80 ⁰ C lying temperatures, until the reaction is substantially complete. The product is isolated by pouring the reaction mixture on ice and then extracting with a suitable solvent such as methylene chloride. The 2-methoxy-4-alkylphenol is then converted to the intended 3-alkylphenol by removal of the phenolic hydroxy group. The process consists in the conversion of the hydroxy group into a dialkyl phosphate group by reaction with a dialkylchlorophosphoate, for example diethylchlorophosphonate, or with diethylphosphonate and triethylamine. By treatment of the dialkyl phosphate with lithium

2 t 82t 4

to / ammonia and subsequent demethylation of the resulting alkylated methyl ether lait boron tribromide or pyridine hydrochloride or other known demethylating the resulting 3-alkylphenol.

A convenient method for preparing compounds of the invention in which -Z-Ws-O-CaIk ₂ ) _n -V7 provides for the use of 4-bromoresorcinol as starting material. The method consists in protecting the two hydroxyl groups of the resorcinol by benzylation according to standard methods. In this method, the benzyl group is preferred as a protective group because it can be easily removed by catalytic hydrogenation without cleavage of the Ither.gruppe -C-CaIk ₂ ) -β . Of course, other protecting groups such as alkyl (eg, methyl or ethyl) may also be used. However, preference is given to the benzyl protecting group since it leads to less side reaction. The protected 4-bromoresorcinol is then subjected to the Grignard reaction and reacted with the appropriate cycloalkenone in an inert solvent in the manner described above. The thus produced 3- (2,4-dibenzyloxyphenyl) cycloalkanone is catalytically hydrogenated over palladium on carbon to give the corresponding 3- (2,4-dihydroxyphenyl) eyeloalkanone, which is in equilibrium with its Heini ketal. The heiaicetal is then converted to the corresponding C 1-10 alkyl, eg, methyl, ketal, by reaction, for example, with a trialkyl orthoformate, such as triethyl thyethormide, in a suitable solvent, such as C 1-4 alcohol, eg, methanol, in the presence of concentrated sulfuric acid , The alkylketal thus produced is then treated with the appropriate alkyl or aralkyl methanesulfonate or tolysate in the presence of anhydrous sodium or potassium carbonate in a suitable inert solvent such as Ν, Ν-dimethyl

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formamide alkylated at a temperature lying between 75 and 100 G. This method has the advantage that simpler compounds can be used for the entire sequence of reactions. The O-alkylated or aralkylated tetradene is then deketalized by reaction with, for example, hydrochloric acid to produce the corresponding 3- (2-hydroxy-4- / U- (alk 2) -7-phenyl) -cycloalkanone which is in equilibrium with its heniiketal.

Since compounds of formulas IA-ID in which A and B taken together are oxo and R 1 is hydrogen are in solution in equilibrium with the hemicetal form and some, in the crystalline state, are substantially perfectly in the hemicetal form, compounds of the formulas IA-ID, in which A and B taken together are oxo and R ^ is hydrogen, to be considered to include the hemiketal as well as the keto form. ·

Compounds of the present invention in which A and B taken together are methylene are readily prepared from the corresponding oxo linkages via the reaction with methylene diphenyl phosphors or other appropriate methylid. The usual method is to produce the Wittig reagent, ie , the methylidene, in situ, and immediately after the production of the methylidene in its reaction with the appropriate oxo compound. A convenient method for the generation of the methylide consists in reacting sodium hydride with dimethyl sulfoxide (sodium dimsyl) at a lie-constricting between about 50 and 80 ⁰ O temperature, usually until evolution of hydrogen has ceased, followed by reaction of the methylsulfinyl incurred (Dimsyl ·) solution with, for example, methyltriphenylphosphonium bromide

follows at a temperature between about 1O ⁰ G and about 80 ⁰ O temperature. The solution generated in this way of the ylide is then added to the appropriate oxo compound and the mixture is located at between room temperature and 80 ⁰ O. Tempera ture stirred. The methylene compound prepared in this manner is isolated by known methods. Hydroboration-oxidation of the methylene compound then gives the hydroxy-ethyl-derivative according to the explanation given here. Borane in tetrahydrofuran is preferred for the hydrobromination step as it is commercially available and gives satisfactory yields of the intended hydroxy methyl compound. The reaction is generally carried out in tetrahydrofuran or diethylene glycol dimethyl ether (diglyme); The Boranprodukii is not isolated, but oxidized directly with alkaline hydrogen peroxide to Hydroxymethylverbindung.

Other methods of producing the methylidene are of course known and may be used instead of the procedure described above. Typical methods are described by Maercker in Organic Reactions, 14, 270 (1965) ¹ ° ~ ^e written. For example, in the oxo linkages of formulas IA-ID, the phenolic hydroxy group can be protected by, for example, reacting in an alkanoyloxy derivative. Of course, other protecting groups can be used. The hydroxyl group can be converted to ether, such as tetrahydropyranyl ethers. However, protection of the phenolic hydroxy group is not necessarily required if sufficient base is present to convert the phenyl hydroxy group to an alkoxide.

Esters of the compounds of the formulas IA-ID, wherein R 1 is alkanoyl

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or -00- (CH ₂ ) HRj-R ₆ can be readily prepared by reacting compounds of Formulas IA-ID wherein R 1 is hydrogen with the appropriate allanoic acid or acid of the formula HOOC- (CH ₂ X ₀ NRc Rk On the other hand, they are obtained by reacting a compound of formula IA-ID with the appropriate alkanoic acid chloride or anhydride, eg acetyl chloride or acetic anhydride, in the presence of a base such as pyridine.

Esters of the compounds of formulas IA-ID wherein A is hydrogen and B is hydroxy or hydroxyethyl and OR 1 is hydroxy are prepared by acylation according to the procedures described above. Compounds in which only the R group (R = OH, CH ₂ OH) is acylated are obtained by mild hydrolysis of the corresponding diacyl derivative, with an advantage in facilitating the hydrolysis of the phenolacyl group. The compounds prepared in this manner may be further acylated with another acylating agent to form a di-esterified compound having various ester groups.

The analgesic properties of the compounds according to the invention are determined by tests using pain-promoting stimulants.

Tests using SchmirmzvermitteInder heat stimulants

a) Analgesic Mouse Assay Using Smooth The procedure employed is a modification of the method of Woolfe and MacDonald, J. Pharmacol. Exp. Ther., 80 , 300 -

218214

(1944). A controlled heat stimulus is allowed to act on the feet of mice placed on a 1/8 inch thick aluminum plate. A 250V / att infrared heater with reflector is placed under the Aluwinuim plate. A thermostat connected to thermistors on the disk surface programs the heat lamp to maintain a constant temperature of 57 ° C. Each mouse is placed in a glass cylinder (6 1/2

dte

Inch diameter), and ki timing starts when the mouse's feet touch the plate. The mouse is observed 1/2 hour and 2 hours after treatment with the test compound for the first "back" movement of one or both hind feet, or for 10 hours without such movement. Morphine has an HPE ^ q of j6 EO-g / kg (subcutaneously).

b) Anaesthetic ^ tail tail-twitch test

The tail-tail test in mice was modified according to D'Amour and Smith, J ^ Pharmacol, Exp. Ther., 72-79 (1941), with regulated high heat acting on the tail. Each mouse is placed in a close-fitting metal cylinder so that the tail sticks out at one end. This cylinder is placed so that the tail lies flat over a covered heating lamp. At the beginning of the test, an aluminum panel is pulled back over the lamp to allow the beam of light to pass through the slot and focus on the tail end. At the same time, a timer is switched on. The latency of a sudden twitching of the tail is determined. Unpolluted mice usually react within 3 to 4 seconds after irradiation with the lamp. The endpoint for protection is 10 seconds. Each mouse will be 1/2 hour and 2 hours after treatment with morphine and the

218214

Test connection checked. Morphine has an MPE ^ q of 3 to 2 to 5.6 mg / kg (subcutaneously).

c) tail method of immersion

The method is a modification of the vascular procedure developed by Benbasset et al., Arch, int. Pharmacodyn., 122 , 434 (1959). Male Albinomau.se (19 to 21 g) of the Charles River CD-1 strain are weighed and identified for identification. For each drug treatment group, usually five animals are used, with each animal acting as its own control. For general investigative purposes, new test agents are initially administered at a dose of 56 mg / kg intraperitoneally or subcutaneously in a volume of 10 ml / kg. Before treatment with the drug and 1/2 hour and 2 hours after administration, each animal is placed in a cylinder. Each cylinder is provided with holes for adequate ventilation and is closed by means of a round nylon plug through which the animal's tail protrudes. The cylinder is held vertically and the tail is completely submerged in the Yifasser bath with constant temperature (56 ⁰ G). The end point of each experiment is an energetic jerky movement or a pulling of the tail in conjunction with a movement reaction. In some cases, the endpoint may be less severe after the drug. To prevent unnecessary tissue injury, the trial is terminated after 10 seconds and the tail removed from the water bath. The reaction latency is noted down to 0.5 seconds in seconds. A vehicle control and standard of known potency are tested simultaneously with the candidate candidates. If the efficacy of a test agent does not return to baseline after the 2-hour test point, reactivity

2 i 8214

onslatenzen after 4 and 6 hours. A final measurement is made after 24 hours if efficacy is still evident at the end of the test day.

Test using chemical pain-stimulating stimulants,

Suppression of phenylbenzoquinone stimulant_indu

gracious twitching

Groups of 5 Carworth Farms CF-1 mice each are pretreated subcutaneously or orally with saline, morphine, codeine or the test compound. Twenty minutes (for subcutaneous treatment) or fifty minutes (for oral treatment) later each group is treated by intraperitoneal injection of phenylbenzoquinone, i. an irritant known to cause abdominal contractions. The mice are observed for 5 hours for the appearance or absence of twitches, starting 5 minutes after the injection of the irritant. The MPE ^ y values of the drug pretreatment to block the twitches are determined.

Tests Using Pressure-Relieving Stimulants Effect on the Haffner Scfowanzkneif Process A Modification of the Haffner Method, Experimental Testing Zest- Resting Agent, Deutsch. Me d.Wschr., 55? No. 731-732 (1929) is used to determine the effect of the test compound on a caustic stimulus induced by a caudal stimulus. Attack reaction used. Male albino rats (50 to 60 g) of the CD strain Charles River (Sprague Dawley) are used. Before drug treatment, and again 1/2, 1, 2, and 3 hours after treatment, a 2.5-inch Johns-Hopkin- ^It Bulldog "cluster is clamped onto the root of the rat's tail, and the endpoint of each trial is clearly indicated -

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gripping and biting behavior against the Disturbing Stimulus, recording the latency of the attack in seconds. The clamp is removed after 30 seconds if no attack occurred, and the latency of the reaction is noted after 30 seconds. Morphine acts at 17.8 mg / kg (intraperitoneally).

Tests using electrical pain-promoting styles

A modification of the Rückzuck-Spring method of Ten, Pysychopharmacagagia, 12, 278-285 0968) is used to determine the pain threshold. Male albino rats (175-200 g) of OD strain Charles River (Sprague Dawley) are used. Prior to administration of the drug, the feet of each rat are dipped in a 20% glycerol / brine solution. The animals are then placed in a chamber and allowed to act on their feet for 1 second shock applied at 30 second intervals of increasing intensity. These intensities are 0.26, 0.39 »0.52, 0.78, 1.05, 1.31, 1.58, 1.86, 2.13, 2.42, 2.72 and 3.04 mA. The behavior of each animal is assessed for (a) twitching, (b) squeaking, and (c) jumping or rapid advancing at the onset of shock. Individual increased series of shock intensities are used in each rat immediately before and 1/2, 2, 4 and 24 hours after treatment with the drug.

The results of these tests are recorded as percentage maximum potential effect (% MPE). The% EPE values of the group are compared statistically with the% MPE value of the standard values and the control values before taking the drug. The IHE values are calculated as follows: «

-28- 2 18214

" Test Duration - Control Duration" Duration of Suspension Control

The compounds of the present invention, when used as analgesics by oral or parenteral administration, are best administered in the form of a composition. Such compositions contain a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. For example, they may be administered in the form of tablets, pills, powders or granules containing excipients such as starch, lactose, certain types of clay, etc. They can be administered as capsules mixed with the same or similar excipients. They may also be administered in the form of oral suspensions, solutions, emulsions, syrups and elixirs which may contain flavoring or coloring agents. For the oral administration of the therapeutic agents of the invention are tablets or capsules containing from about 0.01 to about 10 mg , suitable for most applications.

The physician will determine the amount best suited for a particular patient, and this will vary according to the age, weight and response of the individual patient and the route of administration. In general, however, the initial amount of analgesic in adults will be between about 0.1 and about 750 mg per day in a single dose or multiple doses. In many cases, it is not necessary to exceed 100 mg daily. A favorable oral dose is between about 1.0 and about 300 mg / day, the preferred dose being about 1.0 to 50 mg / day. A favorable parenteral dose is between about 0.1 to about 100 mg /

₂₉ . 2 18214

Day, the preferred between 0.1 and about 20 mg / day.

The invention also relates to unit dose form pharmaceutical compositions which are valuable for the use of the compounds described herein as analgesics and other purposes set forth herein. The dose may be administered once or in multiple amounts, as discussed above, to achieve the daily effective dose for a particular purpose.

The compounds (medicaments) described herein may be formulated for administration in solid or liquid form, for oral or parenteral administration. Capsules containing medicaments according to the invention are obtained by mixing a part by weight of the medicament with nine parts by weight of excipient such as starch or milk sugar and

huTC

Fill the mixture into gelatine capsules, each capsule containing 100 parts of the mixture. Tablets containing these compounds are prepared by admixing suitable mixtures of medicament and standard ingredients as used for the preparation of tablets, such as starch, excipients and lubricants, each tablet containing 0.10 to 100 mg of medicament per tablet.

Suspensions and solutions of these drugs, especially those in which R 1 (Formulas I and II) is hydroxy, are often prepared immediately prior to use to eliminate problems with shelf life of the suspensions or solutions (eg, precipitation) of the medicament upon storage , Compositions suitable for this purpose are generally present as dry solid compositions which are dissolved for administration by injection.

218214

With the aid of the methods explained above, the analgesic activity of various compounds according to the invention is determined. The compounds have the following formula:

Table I: A = H, B = OH; Table II: A + B = oxo.

In the tables, the following abbreviations are used: PBQ, = phenylbenzoquinone-induced writhing; TF = tail twitching; HP = heating plate; RTO = pinching of the rat's tail; and J \ T. = Twitching - jumping »

The individual values in the tables are ED ^ Q values. A number followed by a second number in parentheses indicates the % protection observed at a particular dose. Thus, 31 (56) y \% means protection at the dose of 56 mg / kg body weight.

Table II analgesic activity ED, - _n (nig / kg) of protective (mg / kg) subcutaneously a;

χ B.

1 cis-OH

1 trans-OH

1 cis-OH

1 trans-OH

1 cis-OH

2 trans-OH 2 cis-oH

O cis-OH

0 trans-OH

1 trans-OH 1 trans-OH 1 cis-OH

1 cis-oH

trans-CH.

trans-GH.

trans-CH.

H

C (CH ₃ ) ₂ (CK ₂ ) ₅ OCH (CH.

0 (CH ₃ ) ₂ (CH ₂ ) ₆ "C (CH ₃ ) ₂ (CH ₂ ) ₆ C (CH ₃ ) ₂ (CH ₂ ) ₆ C (CH ₃ ) ₂ (CH ₂ ) ₆

W

H .

° 6 ^H 5

^C 6 ^H 5 H

H H H H

PBQ

HP

FJ RTC

1.1 3.8

28 (56) 38 1.53 IA

1.5

57 (56) 36 (56) 0.5 "

6.8 4.0 4.7

65 (10) 5.4 5.6 27 (10) 32 (10) 3.5 7.7

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-33- 2 1821 4

Your effectiveness as a diuretic ^iu edium is determined by the procedure of Lipschitz, among others, J. Pharmacol, "19 7" 97 (1943), used in the rats as test animals. The dose for this purpose is in the same range as those listed above for the use of the compounds described herein as analgesic agents.

Efficacy as antidiarrheal is by a modification of the procedure of Neimegeers among others, modem Pharmac010gy-Toxic01 οgy, V / i 1 learning van Bever and Harbans LaI, editor, 2 ^"68 - determined 73 (1976), 18 hours before the test Charles River GD-1 rats (170 to 200 g) housed in groups in cages. The animals must fast over Bfacht before administration of castor oil, but water is available at will. The test drug is administered subcutaneously or orally at a constant rate of 5 ml / kg body weight in a vehicle of 5 % ethanol, 5 % Emulphor EL-620 (a polyoxyethylated vegetable oil emulsifier available from Antara Chemicals, New York, NY) and 90 % Brine, followed after one hour by the administration of castor oil (T ml, oral). The animals are housed in small single cages (20.5 x 16 χ 21 cm) • with hanging grid floors. A disposable card sheet is placed under the grid bottoms and examined for the presence or absence of diarrhea one hour after the castor oil dose. A vehicle / castor oil treatment group serves as a control for the daily trial. The results are recorded as the number of animals that were protected one hour after administration. In general, the dose levels when using these compounds as antidiarrhoeal are consistent with those used as analgesics.

-3 * '- 2 18214

The sedative effect of the compounds of the invention is determined by their oral administration to rats in amounts ranging from about 0.01 to about 50 mg / kg body weight and observing the subsequent reduction in spontaneous motor activity. The daily dose in mammals is between about 0.01 and about 100 mg.

The anticonvulsant activity is determined by subcutaneous administration of the test compound to male Swiss mice (Charles River) weighing 14 to 23 g in a vehicle used for the antidiarrheal challenge. The mice are divided into groups of 5 animals each. On the day before the experiment, the mice are given no food for more than eightyears, but at their discretion. Treatments are made in quantities of 10 ml per kg using a 25-gauge injection needle. The test animals are treated with the test compound and one hour thereafter an electroconvulsive shock of 50 mA is applied transcorneally at 60 Hz. At the same time, control experiments are carried out in which the mice receive only the vehicle as a control treatment. The electroconvulsive shock treatment causes tonic extensor muscle convulsions in all control mice with a latency of 1.5 to 3 seconds. Protective effect is noted when a mouse shows no tonic extensor muscle convulsions for 10 seconds after the application of electroconvulsive shock.

The efficacy as an antianxiolant is determined in a similar manner to that for the determination of anticonvulsant activity, except that the convulsion inducing agent pentylenetetrazole was used in an amount of 120 mg / kg when administered intraperitoneally.

- 35 - 2 i 821 4

de. This treatment causes clonic convulsions in less than 1 minute in over 95% of treated control mice. Protection is noted when convulsion latency has been delayed by at least half by drug pretreatment.

Efficacy as a sedative / depressant is determined by subcutaneous treatment of groups of six mice each with different doses of the test agents. At 30 and 60 minutes after pretreatment, the mice are placed on a rotary wheel for one minute and judged for their behavior on the rotary wheel. The inability of the mice to stay on the wheel is taken as evidence of the effectiveness of the sedative / depressant.

Exemplary embodiments: Example 1

2-one

A solution of 2-benzyloxy-4- (1,1-diynylheptyl) benzaldehyde (65.2 g, 0.193 Md) and 1-triphenylphosphoranylidene-2-propanone (62.0 g, 0.047 mol) was added and the'cooking continued at reflux for 24 hours. The reaction mixture was cooled, evaporated and diluted with ether. The resulting precipitate of triphenylphosphine oxide was removed by filtration. The crude oil was purified by column chromatography on 1.5 kg silica gel eluting with 20 % ether-hexane to give 53.9 g (74%) of the title compound as an oil,.

IR: (OHOl ₃ ) 1681, 1621 and 1575 cm ^-1 .

-36- 2 18214

MS: (m / c) 378 (M ⁺ ), 364, 337, 293, 271, 251 and 91

'0.83 ( ^m > terminal methyl), 1.22 (s, acc.

Dimethyl), 2.32 (S, MeGO), 5.17 (s, benzylniethylene), 6.70 (d, J = 16Hz, vinyl H), 6.95 (m, two ArH). 7.38 (m, Ph and ArH) and 7.90 (d, J = 16 Hz, vinyl H).

The remaining 2-benzyloxy-4- (z-W) benzaldehydes of preparation Z are prepared in the same manner to produce the corresponding compounds of formula

Z-W

wherein Z and W are as defined in the preparation.

Example 2:

1 _A 3-cy c 1 ohe xand i ο η

To a solution of sodium methoxide (0.67 g, 12.4 mmol) and dimethylmalonate (1.86 g, 14, 1 mL) in methanol (4.75 mL) was slowly added a solution of trans-4/2 "-1 ^D enzylo: xy-4 - (1,1-dimethylhept-yl) phenyl _i 7-3-buten-2-one (3.75 g, 9.92 mmol) in methanol (4 ml) was refluxed for 3 hours, then cooled and evaporated under reduced pressure The residue was diluted with ether and saturated sodium chloride and acidified with 1N hydrochloric acid The ether extract was washed twice with 500 ml of saturated sodium chloride (500 ml) over magnesium sulfate dried and 4.71 g (91 %) of the

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Title compound evaporated.

Melting point: 108 to 109 ° C (from petroleum ether)

IR: (OHOl ₃ ) 1742, 1709, 1612 and 1577 cm * " ¹ .

MS: (m / o) 478 (M ⁺ ), 446, 419, 393, 387 and 91.

PMR: ^ Q ₁ 0.82 (m, terminal methyl), 1.19 (s, gem. Dimethyl), ³ 2.6-3.1 (m), 3.2-4.2 (m), 5 , 05 (m, benzylmethylene), 5 _t 5? (s, enol vinyl Ii), 6.8 (m, ArH) and 7.35 (m, Ph and ArH).

Analysis: Calculated for 0 ^ _Q E ^ _Q 0 ^: °>75.28; H, 8.00%. Found: C, 75.05; H, 7.97%.

Repetition of this procedure, but using the buten-3-ones of Example 1, gives compounds of the formula shown below, wherein Z and Y / correspond to the definition of Example 1.

xandion

A mixture of 5-Z2 ~ -B ^enz yl ^{o: x} y - 4- (1,1-dimethylheptyl) pheny3.7 -4-carbomethoxy-i, 3-cyclohexanedione (20.8 g, 43.5 mmol) , dioxane (40 ml) and 20% sodium hydroxide (40 ml) was maintained at 100 ⁰ O for 2.5 hours. It was cooled in an ice bath and acidified with concentrated hydrochloric acid. This mixture was heated to 100 ^° C. for one hour.

218214

hold, cooled to O ⁰ O and then neutralized with sodium bicarbonate. The resulting mixture was added to saturated sodium bicarbonate and ether. The ether extract was dried over magnesium sulfate and evaporated to an oil. Purification of this oil by column chromatography on 1 kg of silica gel eluted with 10 % acetone-ether afforded 10.9 S (60 %) of the title compound.

Melting point: 102-103 ⁰ C (from pentane-ether) IR: (Chol ₃₎ 3636-2222 (broad), 1739, 1712, -1613 (broad)

and 1577 (shoulder). MS: m / e 420 (M ⁺ ), 335, .329 and 91.

PMR: ^ j ₁ 0.8 (m, terminal methyl), 1.20 (s, gem.Dimethyl), ³ 2.70 (bdd, J = 10 and 8 Hz, methylene), 3.33

(bs, GOGOGH ₂ CO), 3.6 (m, benzylmethine), 5.0 (s, benzylmethylene), 5.58 (s, enol vinyl H), 6.8 (m, ArH), 7.22 (bs , Ph), and 8.83 (bs, enol-OH).

Analysis: Calculated for G ₂₈ H ₃₆ Oo: C, 79.96; H, 8.63%. Found: C, 79.87; H, 8.54%.

The remaining 4-carbomethoxycycloalkanediones of Example 2 are decarboxylated in the same manner to give compounds of the formula shown below where Z and W are as defined in this example.

Z-W

21B214

5 - ^ - ^ Benzylo'xy-4 (1 _JL 1-dimethylheptyl) gheny] -7--3-methoxy-2-cgclohexen-i-one

A solution of ^ ₁ O g (11.9 mmol) of 5 ~ Z 2 "-Benzyloxy-4- (1,1-dimethylheptyl) phenyl 7-1,3-cyclohexadione and p-toluenesulfonic acid (200 mg) in methanol (250 ml). was refluxed for 30 minutes in a flask connected to a Soxleth condenser containing molecular sieves 3A The reaction mixture was cooled, concentrated under reduced pressure and the residue was diluted with saturated sodium bicarbonate and ether The ethereal extract was washed successively with saturated sodium bicarbonate , saturated sodium chloride, dried over magnesium sulfate and evaporated to 5.15 g (99%) of the title compound as an oil.

IR: (OHOl ₃ ) 1644, 1612, 1503, 1460 and 1379 cm ^-1 . MS: (m / e) 434 (M ⁺ ), 34-9, 343 and 9I.

PMR: ^ ₁ 0.81 (m, terminally methyl), 1.25 (s, gem. Dimethyl), ³ 2.49 (d, methylenes), 3.66 (s, OMe), 5.05 (s , Vinyl H) and 7.28 (s, Ph).

Similarly, the remaining compounds of Example 3 are converted into compounds of formula

 z v

wherein Z and W are as defined in Example 3 and R ^{0 is} -ethyl. Durh exchange of methanol

218214

against ethanol, isobutanol or propanol, the corresponding alkoxy derivative is recovered.

Beispiel_5:

3- ^ ~ ^ ~ 4- ~ Benzglo p _j ^ hen 7-2 ~ cyclohexen · _(j 1 1 ~ dimeth lhegt ^ ^ _l?) - 1 _z on

Having an O ⁰ O solution of the title compound of Example 4, 5 - ^ - JBerizylo3q5r-4R- (1,1-diiiiethylheptyl) phenyl7-3 _T methoxy-2-cyclohezen-1-one (500 mg, ¹ 1,15IQi IOI In ether (20 ml) was added lithium aluminum hydride (20 mg, 0.53 mmol). The reaction mixture was stirred at ⁰ C for 30 minutes, acidified with 1 N hydrochloric acid and stirred for 2 hours at room temperature. The ether phase was removed, washed successively with saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate and evaporated. The crude oil was purified by column chromatography on 100 g of silica gel eluting with 50% ether-pentane to give 353 (76 %) of the title compound as an oil. IR: (CHGl ₃ ) 1681, 1672, 1613, 1575 and 1479 cnT ¹ . MS: (m / e) 404 (M ⁺ ), 319, 313 and 91 *

PM: Q] JJq ₁ 0.86 (m, terminal methyl), 1.30 (s, according to dimethyl), ^ 2.43-2.86 (m, methylenes), 3.70 (m, benzyl) methine), 5.07 (s, benzylmethylene), 6.06 (bd, J = 5Hz, vinyl H), 6.8-7.3 (m, ArH and vinyl H) and 7.36 (s, Ph ).

Using this procedure, the remaining compounds of Example 4 are compounded with the formula:

Z-W

- 41 - 2 1 821 4

converted, where Z and W correspond to the definition in this example.

Example 6:

cy_clohexen-1-one

To an O ⁰ G solution of methyl magnesium iodide. (11 mL of 2.9 M in ether) and tetrahydrofuran (10 mL) was added dropwise a solution of 5-Z.2-benzyloxy-4- (1,1-dimethylheptyl) phenyl-J7-3-methoxy-2-cyclohexene. Add 1-one (3.4-5 g, 7.95 mmol) in tetrahydrofuran (10 mL). The reaction mixture was then warmed and stirred for 2 hours at room temperature, followed by addition to ice-cold 1N hydrochloric acid. After stirring for 20 minutes, hydrolysis was genically extracted with ether. The ether extract was washed with saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate and evaporated. The crude product was purified by column chromatography on 100 g silica gel eluting with 25 % ether-pentane to give 3.08 g (93 %) of the title compound.

Melting point: 60 to 61 ⁰ C (from pentane) IVIS: (m / e) 418 (M ^+), 333, 327, and 91st

PMR: Q ¹ q ^ ₁ 0.83 (s, terminal methyl), 1.25 (s, gem Diinethylen _o), r 1.96 (s, vinyl methyl), 3.68 (s, Benzylmethin), 5.13 (s, benzylmethylene), 5.98 (bs, vinyl H), 6.90 (m, ArH), 7.12 (d, J = 8Hz, ArH), and 7.33 (s, Ph).

In the same way, the following compounds were prepared from the appropriate reactants:

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c ^ clohexen-i-on

(2.83 g, 82 %) in the form of an oil of 5- / ß- benzyloxy-4- (1,1-dimethylheptyl) -phenyl. - 3-methyl-biqq-2-cyclohexen-1-one (3 , 46 g, 7> 97 mmol) and 10.8 ml of 2.94 M ethylmagnesium bromide (in ether).

IR: (CHOI.) 1698, 1666, 1623 and 1582 cm ^-1 .: (M / e) 432 (M ⁺ ), 341 and 91.

PMR. ^ ₁ -JJ 0.83 Cn, terminal methyl), 1.02 (t, J = 7 Hz, methyl), ³ 1.27 (s, gem dimethyl), 2.26 (g, J = 7 Hz, methylene of vinyl ether), 2.58 (n, two methylenes), 3.65 (n, benzylline thin), 5.12 (s, benzylmethylene), 5 »94 (bs, vinyl H), 6.9 (η ,, ArH), 7.12 (d, J = 8Hz, ArH) and 7.39 (s, Ph).

-4- (/) _χ 1 -diynylheptyl) ghen2l, 7-3-n-propyl-2-one

g, 85 %) in the form of an oil of 5- / 2 "-benzyloxy-4- (1,1-dimethylheptyl) phenyl .7-3-Biethoxy-2-cyclohexen-1-one (4.00g, 9, 21 mmol) and n-propylmagnesia broinide (36.8 mmol). IR: (GHCl ₃ ) 1661, 1631, 1612 and 1575 cm ^-1 . MS: (m / e) 446 (M ⁺ ), 355 and 91,

PFiR: Q- ^ ₁ 0.85 (m, terminal methyl), 0.95 (t, J = 7 Hz methyl of Iropyl), 1.29 (s, according to dimethyl), 2.22 (m, methylene) , 262 (n, two methylenes), 3.67 (η, benzylmethine), 5, ^ 4 (s, benzylmethylene), 5.95 (bs, vinyl.H), 6.95 (η, ArH), 7, 13 (d, J = 8 Hz, ArH) and 7.40 (s, Ph).

witches-1-on '

(4.11 g, 92 %) as an oil of 5 ~ Z 2 ~ benzyloxy-4- (1,1-dimethylhepyl) phenyl-7-3-methoxy-2-cyclohexen-1-one (4.00 g, 9 , 21 mmol) and 7.37 ml of 2.5 M n-hexylmagnesiabrabrid (in

2 18214

Ether).

IR: (OHOl ₃ ) 1678, 1.661, 1633, 1618 and 1582 cm MS: (m / e) 488 (M ⁺ ), 403, 397 and 91 ·

-1

ODGl °> 9 ° ^ ⁿ ' ^two ' ^be = ^cmi i ^iales methyls), 1.31 (s, according to dimethyl), 2.28 (n, methylene), 2.61 (η, methylene, 3.70 ( η, benzylniethine), 5.20 (s, benzylmethylene), 6.00 (bs, vinyl H), 7.00 (η, ArH), 7.20 (d, J = 8 Hz, ArII) and 7.46 (s, Ph).

Example 7ί

Compounds having the formula shown below are prepared according to the procedure of Example 6 from the compounds of Example 5. In the formula, Z and V / correspond to the definition in Example 5 and R ₂ is methyl, ethyl, n-propyl, sec-butyl or n-hexyl;

Z-V /

Example 8j_

cyclohexanone

A mixture of 5-Z 1 -Benzyloxy-4- (1,1-dimethylheptyl) phenyl 7 -3-methyl-2-cyclohexen-1-one (1.00 g, 2.39 mmol) and 500 g of 5 % P all ad ium-on-bottom / 50 % water was stirred for 1 hour under a hydrogen atmosphere. A second 500 mg portion of catalyst was added and stirring

218214

Continued for 30 minutes. A third 500-iag portion of catalyst was added and stirring continued for 13 minutes. The reaction mixture was then filtered through sodium bicarbonate and magnesium sulfate and the filtrate evaporated. The residue was purified by column chromatography on 140 g of silica gel eluting with 10 % ether-petroleum ether to give 323 g (32%) of the title compound as an oil

MS: (m / e) 420 (M ⁺ ), 402, 363, 335, 329 and 91.

HvIR QQGi °> ^8δ ( ⁿ J terminal it methyl), 1.28 (s, gem dimethyl), 4 ^ 06 (C-5-methyl), 3.40 (n, benzyl methine), 5.16. (s, benzylmethylene), 6.95 (d, J = 2Hz, ArH), 6.95 (old, J8 and 2Hz, ArH), 7.43 (s, Ph).

Similarly, the remaining compounds of Examples 6 and 7 are reduced to the corresponding 5-R / I-substituted cyclohexanones.

cy_clohexanon

A mixture of 5- / 2 "-benzyloxy-4- (1,1-dimethylheptyl) phenyl .7-3-methyl-2-cyclohexen-1-one (2.83g, 6.77mmol), 1.5 g 5% palladium-on-carbon / 50% water and sodium bicarbonate (2.8 g) in methanol (30 ml) was stirred under a hydrogen atmosphere for 45 minutes The reaction mixture was filtered through diatomaceous earth and the filtrate evaporated under reduced pressure The residue was dissolved in ether, dried with magnesium sulfate and evaporated, and crystallization of the residue from pentane gave 1.15 g (52 %) of the titer compound.

2 18214

Melting point: 95 to 98 ⁰ O.

PMR Q ^ ₁ 0.87 (η, terminal methyl), 1,1 (O-5-methyl), 1,28 (see g2m dimethyl), 3,25 (η, benzylmethine), 5.62 (s , OH), 6.85 (m, ArII), 7.10 (d, J = 8 Hz, ArH). Analysis: Calculated for 0 ₂ 2 ^Η 34 ° 2 ^ί ° »? 9,95; H, 10.37%. Found: 0, 80.22; H, 10.28%.

According to the above procedure, the compounds mentioned below were prepared from suitable reactants of Examples 6 and 7.

^ 1-dime thyheptyl2-2-hydroxyphenyl _] 17-5-ethylcyc] _: o -hexanone

O »34S, 60%) of 5 - ^ - Benzyloxy-4- (1- _f- 1-dimethylhepta) phenyl / 3-ethyl-2-oxy-hexen-1-one (2.83 g, 6.55 mmol). Melting point: 106 to 107 ⁰ O.

IR: (CHGl ₃ ) 3597, 3333, 1709, 1626 and 1585 cm ^-1 . MS: (m / e) 344 (M ⁺ ), 326, 315, 297, 273 and 259.

0.83 (n, terminal methyl), 0.95 (t, J = 7Hz, methyl). ^ 1,25 (s, according to dimethyl), 3,25 (η, benzylmethine). 5.98 (s, OH), 6.90 (n, ArH), and 7.16 (d, J = 8 Hz, ArII). Analysis: Calculated for O ₂₃ H ₀₆ O ₂ : C, 80.18; H, 1Q53 %. Found: O, 80.27; H, 10.39 % ·

(1.66 g, 61%) of 5-z ^ - ^Benz y ^{lo; x} y "- ^{Z |} - ( ^{'1' '1} - 5 ^{diinetti rllie} P ^t y ¹⁾ phenyl-7 ~ 3-propyl-2 cyclohexen-1-one (3.40 g, 7.62 mlvlol.). melting point: 86.5 to 90.5 O. ^0.

IR: (CHOI3) 3533, 3289, I700, 1618 and 1577 cm ^-1 . \

210214

MS: (m / e) 358 (M ⁺ ), 340, 315, 297 and 273.

Emri Q ^ ₁ 0.90 (s, terminal methyl), 1.22 (s, gem. Dimethyl), ³ 3.25 (s, Benzylmethin), 5.95 (s, OH), 6.85 (s, ArH) and 7.14 (d, J = 8 Hz, ArH). Analysis: Calculated for C24 ^H 38 ° 2 ^{: 8O} >39; H, 10.68%. Found: G, 80.16; H, 10.57%.

hexanone

(3.06 g, 93%) of 5-Z ² "- ^Benz y ^lox y-4- (1,1-dimethylheptyl) phenyl ^ 7 ~ 3-hexyl-2-cyclohexen-1-one (4.00 g , 8.2 mmol).

Melting point: 84 to 85 ⁰ G (from pentane).

IR: (OHOl ₃ ) 3571, 3333, 1703, 1623 and 1582 cm ^-1 .

FiS: (m / e) 400 (M ⁺ ), 382 and 315.

Φί / Q

PMR cdoI ° * 9 ° Cn, terminal methyl), 1.21 (s, according to dimethyl), 3.20 (η, benzylmethine), 5.80 (s, OH), 6.85 (η, ArH) and 7.10 (d, J = 8 Hz).

Analysis: Calculated for C ₂₇ H ^ O ₂ : C, 80.94; H, 11.07%. Found: O, 80.97; H, 10.94%.

Example 10:

The compounds of Example 7 are hydrogenated catalyzed by the procedure of Example 9 to give the below-mentioned products wherein Z, W and R ^ are as defined in Example 7.

OH

-47- 2 18214

tr ^ s ~ 3 - ^ - Benzyloxy-4- (1,1 -DIME thy lheptyl) phenyl7-5 ⁱ -inet; hyl · -

Having an O ⁰ O solution of Dimethy! Copper lithium (2.47 mmol) in ether (3 ml) and hexane (2 ml) was added dropwise a solution of 5-Z2-benzyloxy-4- (1,1-dimethylheptyl) phenyl7 Add ~ 2-cyclohexan-1-one (500mg, 1.24mmol) in ether (1.5mL). The reaction mixture was stirred for 15 minutes and then poured into saturated aqueous ammonium chloride (300 ml). The quenched reaction mixture was extracted with three 50 mL portions of ether, the combined extracts of ether were washed with water, saturated sodium chloride, dried over magnesium sulfate and evaporated to give 475 mg (92%) of the title compound as an oil

IR: (CHCl ₃ ) 1704, 1613 and 1577 cm ^-1 . BUS: (m / e) 420 (M ⁺ ), 402, 363, 335 and 329.

PIviR; Q] X) I ^Oj85 ^ ⁿ ' ^terininaLes methyl), 0.96' (d, J = 6 Hz, C-5-methyl) ^ 1,22 (s, according to dimethyl), 3,76 (η, benzylinethyne ), 5.08 (s, benzylmetylene), 6.72-7.05 (m, ArH), and 7.33 (bs, Ph).

Beispiel_12j_

trans-3 ^ 4- (1 _χ 1-dirhione th ^ lhegt ^ l) ₌ 2-hydrox2gheny_1.7-5-raeth2; lcyclohexanone

A mixture of trans-3 - ^ - benzyloxy-4- (1,1-dimethylheptyl) phenylethylmethylcyclohexanone (175mg, 0.417mmol) and 175mg of 5% palladium on carbon / 50 % water in methanol (8th ml) was stirred in a hydrogen gas atmosphere until the hydrogen stopped running. The reaction mixture was filtered through diatomaceous earth and the filtrate was reduced. Evaporated pressure. Crystallize the residue from

- 2 1 @ 2 f 4

Pentane gave 89 mg (64%) of the title compound.

Melting point: 99 to 102 ⁰ O.

BIS: m / e 330 (M ⁺ ), 312, 273 and 245..

Za a -78 ⁰ O-containing solution of trans-3- / 2 ~ benzyloxy-4- (1,1-dime thy lheptyl) phenyl7-5-methylcyclohexanone (300 mg, 10,714 nmol) in methanol (15 ml) - tetrahydrofuran (5 ml) 'was added dropwise sodium borohydride (216 mg, 5.68 mmol) over a period of 1 hours * The reaction mixture was stirred for a further 2 hours at -78 ⁰ O, warmed to room temperature and evaporated under vacuum. The residue was acidified with dilute hydrochloric acid and extracted with ether. The extract was dried over magnesium sulfate, evaporated and the residue was purified by column chromatography on 50 g of silica gel eluting with 30% ether-pentane to give, in the order of elution, 232 mg (77%) of the trans, cis isomer and 54, 9 mg (15 % of the cis, trans isomers were obtained · trans, cis :.

MS: (m / e) 422 (M ⁺ ), 337, 314, 229 and 9I.

PMR ^ q ₁ 0.86 (n, terminal methyl), -J05 (d, J = 7 Hz,

C-5-methyl ^, 1,26 (s, according to dimethyl), 3,70 (η, benzylmethine), 4,05 (η, carbinolmethine), 5,13 (see benzylmethylene), 6,8-7 , 0 (n, ArH) and 7.1-7.6 (n, ArII and Ph) ₆

ice, trans t.

MS: (m / e) 422 (M ⁺ ), 337, 314, 229, 206 and 9I.

^PMR ODOl ° ⁹ ^ ⁿ » ^termi ^ ales methyl), 1.05 (d, J = 7 Hz,

218214

C-5-methyl), 3,1-4,3 (η, benzyl- and carbinolmethylenes), 5,13 Cs, benzylmethylene), 5,40 (s, OH) and 6,8 - 7,7 (η, Ph and ArH). ,

meth.ylcyclohexa.nol und__das _x trans trans isomers A -78 ⁰ O-containing solution of ois-3-Z, 2 "-benzyloxy-4- (1,1-diniethylheptyl) phenyl7-5-methylcyclohexanone (228 mg, 0.543 mmol In methanol (10 ml), sodium borohydride (160 mg, 4.21 mmol) was added over a period of 2 hours, the reaction mixture was allowed to reach room temperature, and then it was added to ether-saturated sodium chloride, and the ether extract was dried over magnesium sulfate The residue was purified by preparative thin layer chromatography on five 20 cm χ 20 cm χ 0.5 μm silica gel plates eluted with 50 % ether-pentane to give 36 mg (16 %) of the trans, trans isomer (R- 0.25, SiIicagel, 33% ether-petroleum ether) and 163 mg (R _f 0.17, silica gel, 33% ether-petroleum ether) of the cis-cis isomer.

1-dimethylheptyl) -2-hydroxyphenyl-cis-5-nieth2; 1'-cyclohexanone

To a -78 ⁰ C having solution of cis-3- / 54-1.1 -Dirnethylheptyl) _{-2-hydroxyphenyl>} 7-5-methylcyclohexanol (896 mg, 2.13 mmol) in methanol (30 ml) is added sodium borohydride ( 805 mg, 21.8 mmol). The reaction mixture is stirred for 1 hour at -78 ⁰ O, warmed to room temperature and added to ether and saturated sodium chloride. The ether extract is dried over magnesium sulfate and evaporated to give an oil. Crystallization from pentane gives 589 mg (65 %) of the Tite! Compound:

-so- 2 18214

Melting point: 113 to 114 ^° C.

IR: (GHOIo) 3636, 3390, 1631 and 1592 a "" ¹ . : (m / e) 332 (M ⁺ ), 314, 24 ?, 229 and 95.

PMR: Q ^ ₁ (m, 0-5 and terminal methyl), 1,21 (s, according to dimethyl), ^ 2,95 (η, benzylmethine), 3,82 (η, oarbinolmethine), 5,62 ( s, OH), 6.82 (n, ArH) and 7.12 (d, J = 8 Hz, ArH).

Analysis: Calculated for C ₂ 2 ^H 36 ° 2 ^; C, 79.46; H ₁ 10.91 % · Found: O, 79.79 »H, 10.62 %.

The following compounds are prepared from appropriate reactants in the same way:

cyclohexanol

(74 S, 74%) of cis -3-Z4- (1,1-dimethylheptyl) -2-hydroxyphenyl7-5-ethylcyclohexanone C1, O0 g, 2.30 mmol).

Melting point: 110 to 111 ⁰ G.

IR: (OHGl ₃ ) 3636, 3367, 1631 and 1587 cm ^-1 .

PMR QQ ^ ₁ 0.90 (n, terminal methyl), 1.22 (s, according to dimethyle), 2.95 (n, benzylmethine), 3.85 (n, carbinolmethine), 5.59 (s, OH ), 6.85 (n, ArH) and 7.10 (d, J = 8 Hz, ArH). Analysis: Calculated for C ₂₃ Ho ₀ O ₂ : G, 79.71; H, 11.05 % . Found: G, 79.41; H, 10.71%.

g ^ lc ^ clohexano1

(0.954 g, 71%) of 018-3 - / ^ (1,1-dimethylheptyl) ^-2-r hydroxyphen5 l7-5-n-propylcyclohexanone (1.34 g, 3 »74 mmol). Melting point: 103 to 104 ⁰ G (from pentane).

2 18214

IR: (OHOl ₃ ) 3636, 3378, 1626 and 1587 cm ^-1 MS: (m / e) 360 (M ⁺ ), 342, 275, 257 and 161.

PMR ^ ₁ 0.90 (η, terminal methyls), 1.22 (s, gem. Dimethyl), ³ 2.95 (η, Benzy thin line), 3.82 (s, Carbinolmethin), from 5.4 to 2 (s, OH), 6.85 (n, ArH) and 7.08 (d, J = 8Hz, ArH).

Analysis: Calculated for ^ AO ^ ^G '79.94; H, 11.18% Found: O, 79.88; H, 11.22%.

hexylcjclohexanol

after purification on silica gel, eluting with 50 % ether-pentane; quantitative yield in the form of an oil with a trace of the trans, trans isomer, cis-3 - ^, 4 "- (1,1-dimethyl-1-hepyl) -2-hydroxyphenyl] -7-5-n-hexyl · cyclohexanone (1.20 g, 3.00 mmol).

IR: (OHOl ₃ ) 3623, 3355, 1626 and 1585 cm ^-1 .

MS: (m / e) -402 (M ⁺ ), 384, 317 and 299.

PMR J ^ Q ₁ 0.90 (n, terminal methyls), 1.22 (s, according to dimethyl), ·> 2.97 (η, benzylmethine), 3.85 (η, carbinolmethine), 4.32 ( n, carbinolmethine of trans, trans isomers), 5.58 Cbs, OH), 6.85 (m, ArH) and 7.09 (d, J = 8 Hz, ArH).

Example 16:

c ^ lohexanol ·

A mixture of trans-3- _i / 2 Benzylo2g ^'- -4- (1, 1-dimethylheptj'! ·) Phenyl7 cis ^ -methylcyclohexanol (220 mg, 0.521 mmol) and 220 mg of 5% palladium-on-carbon / 50 % water in methanol (8 ml / l was stirred under a hydrogen atmosphere for 3 hours).

-52- 218214

stir. The reaction mixture was filtered through diatomaceous earth and the filtrate evaporated. Crystallization of the residue from petroleum ether gave 9I mg (53 %) of the title compound.

Melting point: 111 to 112 ⁰ O..

IR: (CHCl ₃ ) 3571, 3333, 1629 and 1572 cm ^-1 (m / e) 332 (M ⁺ ), 314, 246 and 229.

PMR ^ ₁ 0.85 (n, terminal methyl), 1.13 (d, J = 7 Hz, O-5-methyl ^), 1.26 (s, according to dimethyl), 3.55 (η, benzylmethine , 4.15 tn, carbinolmethine), 5.90 (bs, OH), 6.90 (n, ArH) and 7.20 (d, J = 8 Hz, ArH).

Similarly, the following compounds were prepared in the same way from appropriate reactants:

(20.0 mg, 56%) as an oil of cis-3-Z2 "-benzyloxy ~ 4- (1,1-dimethylheptyl) phenyl _i-l7 ~ tra.ns-5-methylcyclohexanol (45 mg, 0.107 mmol. ) as oil.

High resolution MS: (m / e) 332.2698 (M ⁺ , C ₂₂ II ₃₆ O ₂ ), 314.2635, 247.1657 and 229.1600.

^ £ ^ 222-tran-5-methoxy-clohexanol

(28 mg quantitative yield) of trans-3-1,2-benzyloxy-4- (1,1-dimethyl-heptyl) phenyl-7-trans-5-methylcyclohexanol (36 mg, 0.0853 ml of aol) gives the product as an oil , R-P = 0.35 (silica gel, 50% ether-pentane).

218214

A mixture of 19.5 g (0.0468 mol) of 3- / 2-benzyloxy-4- (1,1-dimethylheptyl) -phenyl-cyclohexanone, 12.3 S sodium bicarbonate, 3.00 g of 10 % palladium on carbon catalyst and 250 ml of ethanol was stirred for 1.5 hours under a pressure of 1 atmosphere of hydrogen. The reaction mixture was then filtered through diatomaceous earth with ethyl acetate, and the filtrate was evaporated to a solid. The crude product was purified by column chromatography on 280 g of silica gel eluted with 20% ether cyclohexane to yield a solid. By recrystallization of this solid from aqueous ethanol, 9.1 g (62 %) of the title product with a melting point of 87 ° were obtained predominantly in the hemicetal form.

HvIR ^ q ₁ 0.8? (m, terminal is methyl), 1.27 (s, according to dimethyl), - ⁵ 1.0 - 2.2 (various multiplets), 3.21 (two proton multiples) and 6.92 (m, ArH). IR: (ICBr) 3226, 1629 and 1580 cm "" ¹ .

(GHOI ₃ ) 3571, 3289, 1704, 1623 and 1575 cm " ³ .

m / e 316 (M ⁺ ), 298, 273 and 231.

Analysis: Calculated for C ₂₁ H ^ O ₂ : C, 79.70; H, 10.19. Found: C, 79.69 »H, 9.89.

The above procedures were repeated but using the appropriate reactants of Example 1 to prepare the following products.

hexanone

in the form of an oil (54 mg, 86%) of 80 mg (0.19 mmol) of 3-hydroxybenzylxy-4- (1,1-dimethylheptyl) phenyl-7-methylcyclo

hexanone. ·.

2 18214

IE: (OHGl ₃ ) 3597, 3390, 1623 and 1572 cm ^-1 MS: m / e (M ⁺ ), 315, 287 and 245.

trans-3 - ^ / 4 "- (1 _χ 1 -öi ^ e thylhe

(825 mg, 99%), melting point 62 to 64 ⁰ G (from pentane re crystallized) of trans-3- _/ / S ~ benzyloxy-4- (1,1-dimethyl heptyl) phenyl] J7-4-methylcyclohe: x : anone (1.05S, 2.50 mmol).

rm.ifs

HvIR GT) Gl 0.84 (m, terminal side chain methyl), 1.28 (s, mp ^ dimethyl) and 6.75-7.2 (m, ArH). IR: (CHGl ₃ ) 3571, 3333, 1721 (weak), 1626 and 1577 cm ^-1 MS: m / e 330 (M ⁺ ), - 312, 288, 273, 245, 203 and 161. Analysis: Calculated for ^G 22 ^H 34 ° 2 ^{: C,} 79.97 H, 10.37. Found C, 80.33, H, 10.30.

(1 i.1 r (0.54 g, 47%), mp 61 to 62 ⁰ G (from pentane) of 3- ^ 2-benzyloxy-4- (1,1-dime-thyl-phenyl / cyclopentanone (1.50 g, 3.83 ml of viol.).

reiiQ

PivIR QtiQi 0 ^{»88 (m} j Seitenkettenterminaliaethyl), 1.29 2.0 (s, gem dimethyl 3.) - 3.0 (m, G-2, 4, 5-lviethylene), 3.70 (ία, Benzylmethin ), 5.90 (s, phenyl), 6.82 (bs, overlaps 6.92, ArH), 6.92 (dd, J = 8 and 2 Hz, ArH), and 7.17 (d, J = 8) Hz, ArH).

IR: (KBr) 3279, 1739, 1621 and 1577 cm "" ¹ . , MS: m / e 302 (M ⁺ ), 283, 217, 189, 175 and 161 _e Analysis: Calculated for C ₂₀ H ₃₀ O ₂ : 0.79.42; H, 10.00. Found: C, 79.65; H, 10.03.

- .21821

Quantitative_output_of_3 - ^ - Hy. (

in the form of an oil of 3-Z 2 * -benzyloxy-4- (2-5-phenylpentyl O 3 ey.)) phenyl-7-cyclohexahone (1.0 g, 2.26 mmol).

PME JI) Gl ¹ * ²⁸ ^ ^d » ^J = ^{6 Hz} > methyl), 2.7 (m, two methylenes), 3 3.12 (m, benzylmethine), 4.30 (m, side chain methine), 6.32 (d, J = 2Hz, ArII), 6.32 (dd, J = 8 and 2Hz, ArH), 6.80 (d, J = 8Hz, ArH) and 7.18 (s, PhH). IE: (CHGl ₃₎ 3571, 3333, 1709, 1623 and 1587 cm "^'1. : m / e 352 (M ⁺ ), 206, 188 and 9I.

in the form of a solid (8.5 g, 94%), mp = 158 ^° C. * (from isopropyl ether) of 3- (2,4-dibenzyloryphenyl) cyclohexanone (16.9 S, 43.7 mmol).

ηρτι / fc

HvIE D-DMSO ¹ ^ ~ 2 »5 (various m), 6.1 -6.8 (various m, ArH and OH), and 6.93 (d, J = 8 Hz, ArH), IEs' (KBr ) 3195, 1631 and 1603 cm " ¹ MS: m / e 206 (M ⁺ ), 188, 163, 149 and I36 Analysis: Calculated for C ^ ₂ ^H 14 ^O 3 * ^{C) 6} ^» ⁸⁸ » ^H » 6.84% Found: C, 69.94; H, 6.78%.

(9.75 S, 48%), of 2.00 g (4.76 mmol) of 3-Z ² "-biolzyloxy-4-.

(1,1-dimethyloctyl) phenyl7cyclohexanon.

Melting point 73 to 8O ⁰ G (from pentane).

PME Q ^ q ₁ 0.83 (m, terminal side-chain methyl), 1.22

(s, gem dimethyl J _s) and 6.85 (m, ArH).

IE: (CHCl ₃ ) 3571, 3333, 1709 (weak), 1626 and 1577 cm ^-1 _e

-56- 2 18214

MSi m / e 330 (M ⁺ ), 314, 312, 287 and 231.

Analysis: Calculated for C ₂₂ H ₃₄ O _2: 0, 79.95; H, 10.37%.

Found: G, 79.97; H, 9.99 %.

(4.22 g, 58%) of 3- (2-benzyloxy-4-t-t) -butyl-phenyl) -gycLohe-

acanone (10.0 g, 0.0298 mol). Melting point: 177 to 178 ⁰ G (from isopropyl ether).

PMS: cJ ^ oD ¹ » ^{25 (s} '" tB ^ y ¹ ) »6,7-6,9 (m, two ArH)

and 7.02 ' ⁶ (d, J = 8 Hz, ArH).

IR: (Or) 3279, 1639 and 1592 cm "" ¹ .

MS: - m / e 246 (M ⁺ ), 231, 228, 215, 213, 203, 199, 176 and 161.

(2.52 g, 45%) of 3-Z2- ^SSE nzylo: ^ - 4- (1,1 ~ diinethylpropyl) phenyl / cyclohexanone (7.50 g, 0.0214 mole), melting point: 165-166 ⁰ G (from isopropyl ether)

PMR: 'fJso-D ^{O> 63} ^ * ^J = 7 ^Hz > terminal methyl), 1,11

(s, gem. Diiae ⁶ thyl), 6.8 (m, arii, OH) and 7.10 (d, J = 8 Hz,

IR: (GHGl ₃ ) 3636, 3401, 1724 (weak), 1634 and 1587 cm ^-1 .

MS: m / e 260 (M ⁺ ) 242, 231, 217, 213 and 161.

Analysis: Calculated for ^ oH24 ° 2 ^{: C} »^ ⁸ » ^ ² » ^H » 9> ² 9 ^ * Found:. G, 78.17i H, 9.22%.

(0.6 g, 11%) of 3-Z2-Bemzyloxy-4- (1,1-dimethylbutyl) phenyl-7-cyclohexanone (7.00 g, 0.0192 mol). Melting point: 101 to 102 ⁰ G (from isopropyl ether)

PMR: oDox 0.82 (m, terminal methyl), 1.25 (s, according to Di

-57- 2 1,821 4

methyl) and 6.80 (m, ArH).

IR: (CHGl ₃ ) 3636, 3401, 1724 (weak), 1634 and 1585 cm ^-1 . MS: m / e 274 (M ⁺ ), 256, 231 and 213.

Analysis: Calculated for O ₁₈ H ₂₆ O ₂ : G, 78.79; H, 9.55%. Found: 'G, 78.78; H, 9.21%.

2-hydroxybenzene 7-4-p_ropy-1-cyclohexanone

(1.0 g, 76 %) in the form of an oil of trans-3-2-benzyloxy-4- (1,1-di-ethylheptyl) -phenyl-7-7- (2-propenyl) cyclohexanone (1.65 g, 3.69 miVIol). , , , ,

IR: (GHGl ₃ ) 3610, 3390, 1718 (weak), 1629 and 1577 cm ^-1 . IIS: m / e 358 (M ⁺ ), 340, 288, 273, 255, 203 and 161.

BEAR: ¹ QSMi ° »9 Cm, terminal methyls), 1.22 (s, according to dimethyle), ³ 6.70 (dd, J = 8 and 2 Hz, ArH), 6.75 (d, J = 2 Hz, Arn) and 6.87 (d, J = 8 Hz, ArH).

(4.0 s, 95%) of 3-z ^ - ^Benz y ^lo: y ^{x / i} -Cifi- ^'dimeth y ^L P ^en1; y ¹⁾ P ^ne nyl / cyclohexanone ^ _f 3 g, 0.0146 mol). Melting point: 124.5 to 125.5 ° G (from pentane) IR: (CHGl ₃ ) 3623, 3378, I7I8 (weak), 1634 and 1587 cm ^-1 . MS: m / e 288 (M ⁺ ), 245 and 231.

Analysis: Calculated for G-] q ^H 28 ° 2 ^{: g} »79.12; H, 9.79 % · Found: C, 79.32; H, 9.53 %.

(quantitatively) of 3- / 2-benzyloxy-4- (1,1-dimethylhexyl) phenyl / cyclohexanone (2.0 g, 5.1 mKiol).

Melting point: 82 to 83 ^° C.

IR: (CHGl ₃ ) 3636, 1634, 1616 and 1585 cm ^-1 .

-5 ⁸ - 2 1 S2f 4

MS: m / e 302 (M ⁺ ), 284, 259 and 23L

HlR: ^ ¹ Q ₁ 0.82 '(s, terminal methyl), 1.23 (s, according to dimethyl), ^' 3.10 (m), 3.55 (m) and 6.83 (m, Ar H). Analysis: Calculated for C ₂₀ H ₃₀ O ₂ : C-, 79.4-2; H, 10.00 % ,. Found: ^ 0, 79.16; H, 9.75 %.

(2.4 g, 61%) of 3-./2"-ßenzyloxy- ^z l- (1,1-dimethylnonyl)

phenyl / cyclohexanone (5.0 g, 11.5 mmol).

Melting point: 72 to 73 ⁰ G.

IR: (OHGl ₃ ) 3650, 3413, 1721 (weak) 1639 and 1595 cm ^-1 .

HRMS: m / e 344.2691 (M ⁺ , O ₂₃ H ₃₆ O ₂ ), 326.2570 and 301.2168.

FMR: Q ^ ₁ 0.87 (m, terminal methyl), 1.28 (s, according to dimethyl), ³ 3.10 (m) and 6.85 (m, ArH).

1 _A 1 -dime thy ideell) -2-hydroxyphe ΐχ ^ / c ^ ohe xano η (880 rag, ^ %), of 3 - / _ 2-benzyloxy-3- (1,1-dimethyldecyl) phenyl / cyclohexanone ( 2.0 g, 4.46 mmol). Melting point: 78 to 79 ⁰ O

IR: (CHCl ₃₎ 3623, 1629, 1616 and 1587 cm "^'1. HRMS: m / e 358.2836 (M ⁺ ,

PFiR: Gi) Cl ° » ⁸⁸ ( ^m > terminal methyl), 1.27 (s, preferably dimethyl) ^ ³ 3.15 (m) and 6.85 (m, ArIi).

3- dime thyroclene c) l) z2- (1.4-9 S, 46%) of 3- ^ 2 "-benzyloxy-4- (1,1-dimethy1-undecyl) phenyl / cyclohexanone (4, 00 g, 8.66 mmol). melting point: 72-73 ⁰ C

IR: (ICBr) 3268, 1629 and 1580 cm ^-1 . MS: m / e 372 (M ⁺ ), 354, 329 and 23I.

218214

fpfiPQ

PMR: QPQ _L 0.87 (m, terminal methyl), 1.24, 3.16 ³ .cm), 3.42 (m) and 6.88 (m, arii) (s, gem dimethyl.). Analysis: Calculated for 0 ₂ 5 ^H 40 ° 2 ^{: C} ' ^8O »59; H, 10.82%. Found: C, 80.70; H, 10.84%.

(1.92 s, 81 %) of 3- / 2-benzyloxy-4- (1, i-dimethylheptyl)

phenyl-7-cyclooctanone (3.02 g, 6.95 mmol).

Melting point: 118 ^° C.

IR: (CHCl ₃ ) 3623, 3356, 1709, 1629 and 1587 cm ^-1 .

MS: m / e 344 (M ⁺ ), 329, 326, 283, 273, 259 and 241.

ms / yes

FMR: JpQ ₁ 0.82 (m, -terminal methyl), 1.27 (s, according to dimethyl), ^ 3.55 (bm, benzylmethine), 6.76 (d, J = 2 Hz, ArII), 6.78 (dd, J = 8 and 2 Hz, ArII) and 7.02 (d, J = 8 Hz, ArH).

Analysis: Calculated: for C ₂ 3 ^H 36 ° 2 ^: ° » ⁸⁰ J ¹⁸ * ^H » ^ ⁰ »53 %. Found: G, 79.92; H, 10.37 %.

witches

(1.15S, 70%) of 3- / 2-benzyloxy-4- (1,1-dimethylheptyl) phenyl-4-4-methyl-2-cyclohexen-1-one (2.10 g, 5.02 mf : Iol).

Melting point: 111 ⁰ C (from diisopropyl ether-petroleum ether) IR (CHCl ₃₎ 3534, 3279, 1667, 1623 and 15 7 cm "^'1.

MS: m / e 328 (M ⁺ ), 313 and 243.

PMR: - ^ q ₁ 0.83 (m, terminal methyl), 1.10 (d, J = 7 Hz, methyl), 1.25 (s, according to dimethyl), 2.6 (m, Methylene), 3.2 (m, methine), 6.32 (bs, vinyl H), 6.63 (s, OH), 6.9 (m, ArII), and 7.08 (d, J = 8 Hz, ArH). Analysis: Calculated for G ₂₂ Ii ₃₂ O ₂ : C, 80.44; H, 9.83 %, Found: C, 80.35; H, 9.67 %.

-ω- 2 18214

and the trans isomer - __ *

To a -40 C solution of ⁰ 43, O g (0.106 MoI) 3-oxy-4- (1,1-dimethylheptyl) phenyl ^ cyclohexanone in 500 ml of methanol and 15 ml of tetrahydrofuran, 8.05 g (in three portions 0.212 mol) of sodium borohydride. The reaction mixture was stirred for one hour at -40 ⁰ O, ⁰ to warm to -10 G to stand and finally quenched by the addition of 100 ml saturated sodium chloride. The quenched reaction mixture was added to 1500 ml of water and extracted with three 450 ml portions of ether. The combined ethereal extract was washed with three 100 ml portions of water and two 200 ml portions of saturated sodium chloride, dried over magnesium sulfate and evaporated to an oil. The oil was purified by column chromatography on 400 g of silica gel eluted with 20 % ether-cyclohexene to obtain, in the order of elution, 5.0 g (12%) of trans-3- ^ 2-benzyloxy-4- (1.1 -dimethylheptyl) phenyl7cyclohexanol.

GJ) Qi °> ⁸ 5 C ^m »terminal methyl), 1.26 (s, according to dimethyl), ^ 3,51 (in, benzylmethine), 4,24 (m, carbinolmethine), 5,15 (s, Benzylmethylene), 6.85-7.26 (m, ArIl) and 7.47 (m, PhH).

IR: (CHCl ₃ ) 3636, 3497, 1629 and 1587 cm ^-1 . MS: m / e 408 (M ⁺ ), 393, 390, 323 and 91 ♦ · -.

Analysis: Calculated for C ₂₈ H ₄₀ O _2: C, 82.30; H, 9.87%. Found: C, 81.98; H, 9.82%.

and 22.2 g (5%) of cis-3- / 2 "-benzyloxy-4- (1,1-dimethylheptyl) -phenyl-7-cyclohexanol.

TTvI ^r -i '

PIviR: QQQx O » ⁸ 5 (m, terminal methyl), 1.28 (s, acc.

QQQx dimethyl), ^ 3.1 (m, benzylmethine), 3.79 (m, "carbinolamine").

218214

thin), 5.12 (s, benzylmethylene), 6.83-7.22 (m, ArH), and 7.42 (s, PhH).

Melting point: 75.5 to 76.5 ⁰

IR: (GHGl ₃₎ 3636, 34-97, 1629 and 1587 cm ^"1. MS: m / e 408 (M ^+), 393, 390, 323 and 91. Analysis: Calculated for 0 ₂ 8 ^H 40 ° ^{2: c} » ⁸² » 30; H, 9.87 %. Found: C, 81.95; H, 9.74%.

The following compounds were similarly prepared from appropriate ketones.

A auntitative yield of Z-3 - ^^ enzy_loxy_-4- _(1-A 1-32 dimeth2lhegt2l2ghenyl ^me ^ ^ll 2i ^c y ^c l ^o i ¹ £ ^ ^a ii ^o lin the form of an oil of 3-Ζ2 """^ ^Θηζ 3 · ^Γ '- ^{ο Γ} 5 "" 4- (1,1-diinethylheptyl) phenyl, 7-3-methylcyclohexanone (200 mg, 0.476 mmol)?.

HCR: Jj ^ Q ₁ 0.81 (m, terminal side chain methyl), 1.23 (s, according to dimethyl), 1.30 (s, O-3-methyl), 3.65 (m, garbinolmethine), 5 , 00 (s, benzyl ether methylenes), 6.6-7.3 (m, ArH), and 7.25 (m, PhH).

IE: (CHGl ₃ ) 3546, 3378, 1603 and 1555 cm ^-1 . M / e (M ⁺ ) 337, 314, 299, 211 and 229.

4-methylcyclohexanol (0.225 g, 14 %) in p.a. of an oil and 1.19 S (74%) of the ice, trans-isonating trans-3-dimethyl), 3.41 (m, benzylmethine), 4 , 10 (m, garbinolmethine), 5.17 (s, benzylmethylene), 6.8 - 7.2 (m, ArH), 7.18 (d, J = 8 Hz,

ArH) and 7.45 (bs, PMI). ·

IR: (CHGl ₃₎ 3534, 3390, 1613 and 1572 cm "" ^1).

MS: m / e 422 (M ⁺ ), 337, 331, 314, 246, 229 and 9I.

(1.51S, 76 %) and the trans isomer (0.379g, 19 %)

- ⁶² - 2 1821 4

Form of oils of 3-2-Behzylo: xy-4- (2- (5-phenylpentylo: xy))

phenyl-cyclohexanone (2.0 g, 4.52 mmol). trans;

BUR: ^ _{1 1} 1.28 (d, J = 6 Hz, methyl), 2.68 (m, benzyl)

methylene), ^ 3.45 (m, benzylmetin), 4.22 (m, carbinolmethine), 4.30 (m, side chain methine), 5.09 (see benzyl ether methylene), 6.45 (dd, J = 8 and 2Hz, ArH), 6.55 (bs, ArIi) 7.10 (d, J = 8Hz, ArH), 7.25 (s, PhH) and 7.45 (bs, PhH).

IR: (OHGl ₃ ) 3571, 1613, 3448, and 1590 cm * " ¹ .

MS: m / e 444 (M ⁺ ), 298, 280, 190 and 91.

EMR: Q ^ ₁ 1.25 (d, J = 6Hz, methyl), 3.0 (m, benzylmehine), 3.77 (m, carbinolmethine), 4.38 (m, side chain methine), 5.10 ( s, benzyl ether methine), 6.50 (dd, J = 8 and 2 Hz, ArH), 6, 8 (bs, ArH), 7.12 (d, J = 8 Hz, ArH), 7.32

(s, ArII) and 7.43 (s, PhH).

IR: (CHCl ₃ ) 3571, 3390, 1613 and 1587 cm ^-1 .

MS: m / e 444 (M ⁺ ), 298, I90 and 9I.

c is- 3- ^ 2 ~ B e η zy 1 oxy-4- (1 _A 1 -d iraet h ^ lo c ty 1) ghe n ^ jL / c ^ c 1 oo x aol (1,35 S, 45% ) and the tran s isomer (o, 34 g, 11%) of 3.00 g (7.14 mmol) of 3-Z ^ - ^Benz y ^{lo: x} y ~ ^ - (1,1-dimethyloctyl) phenyl / cyclohexanone and 0.90 g (30%) of a cis-trans mixture

t rans; ,

PMR: QQGi " ⁸ 7 ( ^m > terminal side chain methyl), 1.25 (s, according to DiAethyl), 3.50 (m, benzylmethine), 4.22 (m, carbinolmethine), 5.15 (s, benzylethermethylene ) and 6.8-7.6 (m, ArH and PhH).

IR: (CHCl ₃₎ 3497, 1623 and 1582 cm "^'1. MS: m / e 422 (M ⁺ ) and 323.

-63 - 2 1 821 4

'PMR: ODOl' ⁸ ^ ^ ^m »terminal side-chain methyl) 1.25 (see according to dinaethyl), 3.10 (m, benzylmethine), 3.75 (m, oarbinolmethine), 5.12 (s, benzylethermethylene ), 6.91 (dd, J = 8 and 2 Hz, ArII), 6.91 (d, J = 2 Hz, ArH) 7.17 (d, J = 8 Hz, ArH) and 7.42 (bs , PhH)

IR: (OHOl ₃ ) 3571, 3425, 1618 and 1577 cm ^-1 , m / e 422 (M ⁺ ) and 323.

(7.18 s, 59%) and the trans isomer (1.33 S, 11%) and 1.5 g (12 %) of a mixture of cis and trans isomers from 12.0 s (0, 0357 mol) 3- (2-benzyloxy-4-t-butylphenyl)

cyclohexanone.

Melting point: 78 to 79 ⁰ O (from hexane)

PM: Q 1, Q _1, 1,30 (s, t-butyl), 3,10 (m, benzylmethine), 3,72 (πι, carbinomethyl), 5,12 (s, benzylethermethylene), 6,97 (d, J = 2Hz, ArH), 6.97 (dd, J = 8 and 2Hz, ArH), 7.17 (d, J = S Hz, ArH) and 7.40 (bs, PhH). IR: (CHOl ₃ ) 3636, 3472, 1621 and 1582 cm ^-1 . MS: m / e 338 (M ⁺ ), 323, 320, 230, 215 and 9I. Analysis: Calculated for C23 ^H 30 ° ^{2: G} '81.61; 8.93 %, Found: C, 81.79; 8.77 %.

trans:. ,

EMR: Q ^ q ₁ 1.23 (s, t -butyl), 3.50 (m, benzylmethine), 4.20 (m, oarginylmethine), 5.02 (s, benzylethermethylene) and 6.8 - 7.4 (m, ArIi, and PhE).

IR: (OHCl ₃ ) 3650, 3 ^ 72, 1626 and 1587 cm ^-1 MS: m / e 338 (M ⁺ ), 323, 320, 230 and 9I.

218214

(6.3 S, 78%) and the trans isomer (1.0 g, 12%) in the form of oils from 8.0 g (0.0229 mol) of 3-Z2-benzyloxy-4- (1.1 ~ dimethylpropyl) phenyl7cyclohexanon.

ice; ,

PMR: ^ ₁ 0.67 (t, J = 7 Hz, terminal methyl), 1.26 (s, according to di 'methyl), 3.05 (m, benzylmethine), 3.75 (m, carbinol methine), 5.15 (s, benzylethermethylene), 6.92 (d, J = 2Hz, ArH), 6.92 (dd, J = 8 and 2Hz, ArH) 7.17 (d, J = 8Hz, ArH ) and 7.42 (bs, PhH).

IR; (CHGIo) 3636, 3344, 1626 and 1587 cm " ¹ .

MS: m / e (M ⁺ ), 337 ,. 334, 323, 244, 215 and 9I.

trans:

IR: (OHOl ₃ ) 3636, 1626 and 1587 cm " ¹ ..

MS; m / e 352 (M ⁺ ), 337, 334, 323, 244, 215 and 9I.

(4.16 g, 52 %) and the trans isomer (0.38 g, 11%) and 0.49 g (6.1 %) of a mixture of cis and trans isomers in the form of oils from Figure 8, 0 g (0.022 mol) of 3- / 2-benzyl-oxy-4- (1,1-dimethyl-butyl) -phenyl-cyclohexanone. ice;

PMR: ¹ QjX) I ⁰ J ⁸⁰ C ^m '' terminal methyl), 1.23 (s, according to dimethyl), ^J 3.05 (m, benzylmethine), 3.70 (m, oarbinol methine), 5.08 (s, BenzylätheriTiethylen), 6.86 (d, J = 2 Hz, ArIi), 6.86 (dd, J = 8 and 2 Hz, ArH), 7.11 (d, J = 8 Hz, ArH) and 7.35 (bs, PhH).

IR: (OHOl ₃ ) 3623, 3448, 1621 and 1582 cm ^-1 . MS: m / e 366 (M ⁺ ), 351, 348, 323, 258, 215 and 9I. trans: /

PIvIR: Q ^ q ₁ 0.83 (m, terminal methyl), 1.22 (s, according to dimethyl), *> 3.40 (m, benzylmethine), 4.18 (m, carbinolmethine), 5.09 (s, benzylethermethylene), 6.86 (d, JS 2Hz, ArH), 6.86 (dd, J = 8 and 2Hz, ArH), 7.11 (d, J = 8Hz,

, -65- 2 18214

ArH) and 7.39 (m, PhH).

IR: (OHGl ₃ ) 3623, 34-72, 1623 and 1585 cm ^-1 .

MS: m / e 366 (M ⁺ ), 351, 348, 323, 258, 215 and 91.

tr-3/2-benzene 1-oxy-4- (1-1-dime thy lhep ^ OplienyjJZc is-4- (2-o-enyl ene) cy_clohexanol

(1 »9 g» 13%) and the cis-3 _T trans-4 isomer - (7.3 g, 51 %) in the form of oils of trans-3-2-benzyloxy-4- (1,1- dimethylheptyl) phenyl7-4- (2-propenylcyclohexanone (14.3S, 32.1mmol).) The order of elution on silica gel with a 2: 1 mixture of pentane and ether gave the trans- 3

c is -4 isomers of the title compound in the form of an oil, followed by the cis-3-r trams-4 isoniere

Trans-3-cis-4-Isorae res:

IR: (GHGI ₃ ) 3559, 3401, 1639, 1608 and 1567 cm ^-1

MS: m / e 448 (M ⁺ ), 443, 430, 363, 406 and 91.

PMR: Q ^ Q ₁ 0.82 (m, terminal methyl), 1.25 (s, according to dimethyl), ^ 3.30 (m, benzylmethine), 4.12 (m, carbinoolmethine), 4.6- 5.0 (m, vinyl H), 5.06 (s, benzylmethylene), 5.2-6.1 (m, vinyl H), 6.82 (d, J = 2Hz, ArH), 6.82 (dd, J = 8 and 2 Hz, ArH), 7.07 (d, J = 8 Hz, ArH) and 7.38 (bs, Ph). cis-3, trans-4 isomer:

IR: (CHCl ₃ ) 3571, 3401, 1639, 1610 and 1572 cm ^-1 .

MS: m / e 448 (M ⁺ ), 406, 363 and 91.

PMR: JJo ₁ 0.82 (m, terminal methyl), 1.22 (s, according to dimethylene), ^ 2.90 (m, benzylmethine), 3.73 (m, carbinolmethine), 4.6-5, 1 (m, vinyl H), 5.02 (s, benzylmethylene), 5.3-6.3 (m, vinyl H), 6.75 (d, J = 2Hz) ArII), 6.75 (dd , J = 8 and 2 Hz, ArH), 6.99 (d, J = 8 Hz, ArH) and 7.25 (bs, PH).

1-dimethylhexyl) phenyl-7-tr ans-4

- 66- 2 1821 4

(495 mg "82%) and the trans-3, cis-4-isomers (105 m £ ₅ 18%.) Of trans-3-Z ^ - ^Be nzyloxy-4- (1,1-dimethylheptyl) phenyl]. 7-2-butenyl cyclohexanone (600 day, 1,3OMiOl). The ¹ trans-3, ice-4 isoin was first eluted. trans - 3 ^<z i cis-isomer; MS: m / e 462 (m ⁺ ), 447, 444, 377 and 91. cis-3, trans-4 isomer: ·

IR: (OHOl ₃ ). 3610, 3448, 1618 and 1577 cm ^-1 . MS: m / e 462 (M ⁺ ), 447, 444, 377 and 91.

and the t rans-3, cis-4 isomer of trans-3- (2-benzyloxy-4- (1 ', 1-dimethylhephenyl) phenyl) -4- (2-pentenyl) cyclohehanone (497 S, 1 In the order of elution, 84 mg (17 %) of the trans-3, cis-4 isomer (Rf = 0.26, silica gel, 33 % ether-pentane) and 363 mg (73 %) of the cis-3, trans-4 isomers (Rf = 0.13, silica gel, 33% ether-pentane).

(5.0 g, 83 %) and the trans isomer 0.60 g, 10 %) in the form of oils of 3- / ß ->> Qnzjloxy-M ^ - (^ , 1-dimethy 1 pentyl) phenyl /

cyclohexanone (6, O g _s 58 mmol).

trans;

IR: (CI IOL ₃₎ 3636.3497, 1623 and 1582 cm "^'1.

MS: m / e 380 (M ⁺ ).

• PMC

PMR :, Q ^ g ₁ 0.83 (m, terminal ethyl), 1.24 (s, according to dimethyl), ^ 3.5 (m, benzylmethine), 4.20 (m, oarbinolmethine), 5, 09 (s, benzylmethylene) and 6.8-7.6 (m, ArE),

IR: (GHCl ₃ ) 3636, 1621 and 1580 cm ^-1 . MS: m / e 380 (M ⁺ ).

2 t8214

PMR: QpI ₁ 0.75 O, terminal methyl), 1.14 (s, according to dimethyl),? 2.90 (m, benzylmethine), 3.52 (m, carbinolmethine), 4.80 (s, benzylmethylene), 6.49 (dd, J = 8 and 2 Hz, ArH), 6.49 (d, - .J = 2Hz, ArH), 6.72 (d, J = 8Hz, ArH) and 6.96 (bs, Ph). ,

(3.0 g, 43%) and the trans-isomer (660 mg, 9%) in the form of oil of 3-Z2 "-B ^e Q ² y3.oxy-4- (1,1-dimethylhexyl) phenyl7 cyclohexanone (7.0 g, 17.9 mmol).

IR: (CHCl ₃ ) 3623, 3448, 1618 and 1575 cm ^-1 .

IVlS: m / e 394 (M ⁺ )

PIvIR: ^ q ₁ 0.82 (m, terminal methyl) 1.22 (s, according to dimethyl), ^ 3.07 (m, benzylmethine), 3.70 (m, carbinolmethine), 5.08 (s , Benzylmethylene), 6.88 (dd, J = 8 and 2 Hz, ArIi), 6.88 (dd, J = 8 and 2 Hz, ArH), 6.88 (d, J = 2 Hz, ArIi), 7.12 (d, J = Hz, ArIi) and 7.37 (bs, Ph), trans:

IR: (CHCl ₃₎ 3623, 7448, 1618 and 1577 cm "^'1. S: m / e 394 (M ⁺ )

0.80 (m, terminal methyl), 1.27 (s, according to dimethyl) ^ 3.42 (m, benzylmethine), 4.12 (m, carbinolmethine), 5.02 (s, benzylmethylene), 6, 83 (m, ArH), 7.04 (d, J = 8 Hz, ArH) and 7.34 (bs, ArH).

(5.0 g, 59 %) and the trans isomer (1.0 g, 12 %) in the form of oils of 3- / benzyloxy-4 - (1,1-dimethylnonyl) phenyl.7cyclohexanone ( 8.5 g, 19.6 %).

ice; , ·.

IR: (CHCIo) 3623, 3 ^ 48, 1618 and 1577 cm ^-1 .

.68- 2 10214

: m / e 436 (M ⁺ ).

PMR: Q ¹ QQ ₁ 0.83 (m, terminal methyl), 1.22 (s, according to dimethyl), ^ 3.04 (in, benzylmethine, 3.67 m, garbinolmethine), 5.08 (s, Benzylmethylene), 6.87 (dd, J = 8 and 2Hz, ArH), 6.87 (d, J = 2Hz, ArIi) and 7.05-7.4-5 (m, ArH and Ph). trans _: _ -

IR: XCHOlo) 3610, 3448, 1618 and 1575 cm ^-1 . MS: m / e 436 (M ⁺ ) ''

0.82 (m, terminal methyl), 1.22 (s, according to dimethyl), - ^ 3,4-2 (ία, benzylmethine), 4.16 (m, garbinolmethine), 5.02 (s, benzylmethylene ) and 6.7-7.5 (m, ArII, and Ph).

(3.5 g, 50 %) and the tjcan s-isomer (1.0 g, 14 % in the form of oils of 3 - / ^ - ^ Qnzyloxj - ^ (^ , i-dimethylundecyl ^ henyl / cyclohexanone (7, 00 g, 15.0 mmol).

IR: (GHOl ₃ ) 3636, 3448, 1621 and 1582 cm ^-1 .

MSs m / e 464 (M ⁺ ).

φ WQ

Bffi: 5d01 ^Ο ' ⁹ ^ ^ ^m ' ^terminal methyl), 1.33 (s, according to dimethyl), 3, 09 (m, benzylmethine), 3.70 (m, garbinolmethine), 5.20 (s, benzylmethylene ), 6.99 (dd, J = 8 and 2 Hz, ArH), 6.99 (dd, J = 8 and 2 Hz, ArH), 7.22 (d, J = 8 Hz, ArII) and 7, 50 (bs, PhH)

 trans:

IR; (CHOl ₃ ) 3534 (wide), 1618 and 1577 cm ^-1 . MS: m / e 464 (M ⁺ ).

(TO jiq

PMR: J ^ q ₁ 0.85 (m, terminal methyl), 1.22 (s, according to dimethyl), 3.48 (m, benzylmethine), 4.17 (m, benzylmethine), 5.08 ( s, benzylmethylene) and 6,7 ^ -7 ^ 3 (m, ArH and Ph).

-69- 2 1821 4

(2.66 g, 59%) and the trans isomer (0.36 g, 8%) in the form of oils of 0- / 2 "-benzyloxy) -4- (1,1-dimethydecyl) phenyl

cyclohexanone (4.5 g, 10.0 mmol).

IR: (OHCl ₃ ) 3704, 3571, 1639 and 1597 cm ^-1 .

MS: m / e 450 (M ⁺ )

PFiR: Q ¹ ^ ₁ 0.86 (m, terminal methyl), 1.25 (s, according to di methyl), 3 3 ^ 08 (m, benzylmethine), 3.74 (m, carbinol methine), 5.08 (s, benzylmethylene, 6.88 (dd, J = S and 2Hz, ArH), 6.88 (d, J = 2Hz, ArH), 7.12 (d, J = 8Hz, ArH) and 7 , 37 (bs, Ph).

trans:

IR: (OHOl ₃ ) 3623, 3448, 1616 and 1577 cm ^-1 . MS: m / e 450 (M ⁺ )

PMR: oÜQi Ο » ⁸² ( ^m > terminal methyl), 1.22 (s, according to dimethyl), 3.53 (m, benzylmethine), 4.22 (ία, carbinolmethine), 5.02 (s, benzylmethylene ) and 6.8-7.6 (m, ArH and Ph).

(1.36 g, 19 %) and the trans isomer (4.12 g, 59 %) in the form of oils of 3- / 2-benzyloxy-4- (1,1-dimethylheptyl) phenyl_7-cyclooctanone (7.0 g, 16.1mRiol)

MS: m / e 436 (M ⁺ ), 421, 418, 351, 328, 300, 243 and 91.

PIvIR: ^ ₁ 0.83 (m, terminal methyl), 1.28 (s, according to dimethyl), 3, ^ 9 (bm, benzylmethine), 3.89 (bm, oarbinolmethine), 5.10 (s, Benzylmethylene '), 6.83 (m, ArH), 7.08 (d, J = 8Hz, ArII) and 7.38 (m, Ph)

trans: · ..... · MS: m / e 436 (M ⁺ ), 421, 418, 351, 328, 243 and 91.

- 70 - 2 1821 4

0.83 cm, terminal methyl), 1.28 (s, acc

 Dimethyl), ^ 3,4 (bm, benzylmethyne), 3,9 (^, garbinolmethine), 5,10 (s, benzylmethylene), 6,85 (m, -ArH), 7,08 (d, J = 8 Hz, ArH) and 7.36 (m, Ph).

Beisgiel 19

cis-3 - ^^ (1χΐ-dimethylhegtyl) -2-hydroxyphenyl / cyclohexanol A mixture of 22.0 g (0.0539 mol) of cis-3- _< / 2-benzyloxy-4- (1, i-dimethylheptyl) -phenyl cyclohexanol, 12.0 g of sodium bicarbonate, and 2.0 g of 10 % palladium on charcoal was stirred for 2 hours under one atmosphere of hydrogen The reaction mixture was filtered through ethyl acetate with ethyl acetate, and the filtrate was evaporated to a solid The solid was recrystallized from hexane to give 13.2 g (77%) of the title product, having a melting point of 109 to 110 ⁰ .

φΤι / Ι <3

PMR: οχίσΐ. ° ^'81 ^ ^{m> terminal} methyl), 1.25 (s, acc

 Dimethyl), ^ 2.80 (bm, benzylinethyne), 3.80 (bm, carbinolmethine), 5.4 (broad, OH), 6.63 (bs, ArH), 6.77 (dd, J = 8 and 2Hz) and 6.87 (J = 8Hz, ArH)

IR: (CHGl ₃₎ 3610, 3356, 1626 and 1582 cm ^"1

MS: m / e 318 (M ⁺ ), 300, 233 and 215.

Analysis: Calculated for ^G 21 ^H 34 ° 2 ^{: C} > 79 » ¹ 9ί ^Η > ^ 0.76

 Found: C, 78.96; H, 10.59.

Following the above procedure, the compounds listed below were prepared from appropriate reactants of Example 18.

(2.47 g, 71%), mp 124-125 ⁰ C (from pentane) of trans-3/2 "-benzyloxy-4- (1,1-dimethylheptyl) phenyl-7-cyclohexanol (4.50 g, 0.011 mol) ,

-71- 2 10214

PMR: Q ^ ₁ 0.81 (m, terminal methyl), 1.25 (s, according to dimethyl), ^ 3.25 (m, benzylmethine), 4.22 (in, carbinolmethine), 6.81 (i.e. , J = 2 Hz, ArH), 6.81 (dd, J = 8 and Hz) and 7.08 (d, J = 8 Hz, ArH)

IR: (CHOl ₃ ) 3610, 3390, 1626 and 1575 cm ^-1 , MS: m / e 318 (M ⁺ ), 300, 233 and 215.

Analysis: Calculated for C ₂₁ H ₃₄ O _2: C, 79.19; H, 10.76. Found: C, 78.82; H, 10:43.

Eine_quantitative_Ausbeute Z-3-2-hyJ.roxyjpheny ^ 7-3-me thy! Cyclohexanol Schmelzounkt 90 to 9I ⁰ C (recrystallized from petroleum ether) of Z-3- / 2 "-benzyloxy-4- (1, 1-dimethylheptyl ) pheny3.7_3-methylcyclohexanol) "(180 mg, 0.246 mmol).

PMR: Q ^ ₁ 0.85 (m, terminal side-chain methyl), 1.25 (s, according to dimethyl), 1.33 (s, C-3-yl-methyl), 3.65 (m, carbinolmethine), 5, 48 (bs, OH), 6.63 (d, J = 2Hz, ArH), 6.82 (dd, J = 8 and 2Hz, ArII) and 7.19 (d, 8Hz, ArH). IR: (CHCl ₃ ) 3597, 3333, 1605 and 1570 cm ^-1 . MS: m / e 332 (M ⁺ ), 314, 299, 286, 271, 247 and 229. Analysis: Calculated for 0 ₂ 2 ^Η 36 ° 2 ^{ί C} »79.45 { ^H > 10.92 Found: C, 79.24, H, 10.64.

A quantitative yield of th2lheptyl) -2-hydroxy ^ henyl £ 7 "4-methylcyclohe2canol _JL melting point 134 ° to 135 ° C (from pentane) of trans, trans-3- / 2 ~ benzyloxy-4- (1,1 -dimethylheptyl) phenyl7-4-methylcyclohexanol (I90mg, 0.450mmol).

Hffi: QQQi 0.7-0.9 (m, C-4 and terminal side chain

thyle), ^ 1.24 (s, according to dimethyl), 3.00 (m, benzylmethine), 4.22 (m, carbinolmethine), 6.78 (d, J = 2 Hz, ArH), 6.88 (d, d,

-72- 2 18214

J s 8 and 2 Hz, ArH) and 7.02 (d, J = 8 Hz, ArH). IR: (GliOl ₃ ) 3571, 3333, 1626 and 1575 cm ^-1 . MS: m / e 332 (M ⁺ ) 317, 314, 247, 233 and 229. Anal. Calcd. For O ₂₂ H ₃₆ O ₂ : C, 79.46; H, 10.92 %. Found: 0, 79.13 »H, 10.68%.

A quantitative yield of cis _i trans- _: 3 _{:: j} / ^ (_ 1 _A 1 _:: Dime

Melting point 150 to 151 ⁰ O, (from pentane), from cis, trans-3/2-benzyloxy-4-2,72 mlol).

FMR: ^ ₁ 0.72 (d, J = 6 hz, O-4-methyl), 0.86) m, terminal side chain methyl), 1.24 (s, according to dimethyl), 2.62 (m , Benzylmethine), 3.77 (m, carbinolmethine), 6.70 (d, J = 2Hz, ArH), 6.83 (dd, J = 8 and 2Hz, ArH) and 7.04 (d, J = 8 Hz, ArH).

IR :. (Chol ₃₎ 3571, 3333, 1621, 1605 and 1580 cm ^"1. MS: m / e 332 (M ^+), 314, 272, 247, 233 and 229. Analysis: Calculated for: C ₂ ^H 2 36 ° 2 ^: 79.46; H, 10.92 Found: O, 79.15, H, 10.72.

cis-3- _< / 4 ₌ (12,1-dime th2lhept2; l) -2-h2droxygheny ^ 7cyclopentanol (464 mg, 55%) and 288 mg (27%) of trans isomer as oils of a mixture of ice - and. Trans-3/2 * -benzyloxy-4- (1,1-dimethylheptyl) phenyl-7-cyclopentanol (1.10g, 2.79mmol).

- ~ fTTp IO

P] VlR: Q- ^ ₁ 0.83 (m, side chain terminal methyl), 1.24 (s) according to dimethyl), 3.2 (m, benzylmethine), 4.52 (m, garbinolmethine), 6.75 ( dd, J = 8 and 2 Hz, ArH), 6.81 (bs, overlaps

6.75, ArH) and 6.97 (el, J = 8 Hz, ArH). IR: (CHGl.) 3571, 3300, 1623 and 1567 cm ^-1 .

-73- 2 10214

MS: m / e 304 (M ⁺ ), 286, 219, 201 and 159. trans::

^ 0.83 (m, side chain terminal methyl), 1.27

(s, according to Dinrethyl), 3.60 (m, benzylmethine), 4.55 (m, Garbinolmethin), 6.78 (bs, overlaps 6.88 (dd, J = 8 and 2 Hz, ArH) and 7 , 10 (d, J = 8 Hz, ArH).

IR: (OHCl ₃ ) 3571, 3333, 1621 and 1575 cm ^-1 .

MS: m / e 304 (M ⁺ ), 286, 219 and 201.

A quantitative yield of

Melting point ^ to 57 ⁰ G

of trans ~ 3- / 2 "-benzyloxy-4- (1,1-di-ethylheptyl) phenyl / cycloheptanol (695mg, 1.64mmol).

mrwic

FMR: YY yy ₁ 0.88 (m, terminal methyl), 1.22 (s, according to dimethyl), ^ 3 _f 20 (m, benzylmethine), 4.22 (m, carbinol methine), 6.85 (dd, J = 8 and 2 Hz, ArII), 6.90 (bs, overlaps

6.85, ArH) and 7.13 (d, J = 8 Hz, Ar II) IR: (GHOl ₃ ) 3333, 1621 and 1570 cm ^-1 . MS: m / e 332 (M ⁺ ), 314, 247 and 229.

Analysis: Calculated for C ₂₂ II ₃₆ O ₂ : 0, 79.46; H, 10.92. Found: C, 79.68; H, 10.62.

A quantitative yield of cis-3-Z ^ - (1,1-DimethyIneptyl) -

2-hydroxyphenyl 7cyclohe ptanol _t Melting point 103 to 104 ⁰ G (rekristalliert from pentane) of _cis-3-y / 2 ~ Benzylo xy-4- (1,1-dimethylheptyl) phenyl7cycloheptanol (380 mg, 0.900 mmol).

HlR: ^ ₁ 0.83 (m, terminal methyl), 1.20 (s, according to dimethyl), 3.0 (m, benzylmethine), 4.0 (m, carbinolmethine), 6.72 (bs, overlaps 6.81, ArH), 6.81 (dd, J = 8 and 2 Hz, ArH) and £, .08 (d, J = 8 Hz, ArH)

IR: (GHGl ₃₎ 3571, 3311, 1621, 1605 and 1580 cm ^'1.

2 182-1 4

: m / e 332 (M ⁺ ), 314, 247 and 229. Analysis: Calculated for C ₂ 2 ^H 36 ° 2 ^{: G} »79.46; H, 10., 92 Found: 0, - 79.39; H, 10.72

A quantitative yield of 2

gphenylpent2; lox2) -) -benzylcyclohex8iol, m.p. 80-84 ⁰ G (pentane) of cis-3 - /, 2 "-benzyloxy-4- (2- (5-phenylpentyloxy)) phenylcyclohexanol (1.15 pbw) , 3.27 mmol).

PMR: ^ ¹ Q ₁ 1.25 (d, J = 6 Hz, methyl), 3.75 (m, carbinol methine), 4.20 (m, side chain methine), 6.23 (bs, ArH), 6 , 40 (dd, J = 8 and 2 Hz) and 6.98 (d, J = 8 Hz, ArII) and 7.13 (s, Ph).

IE: (CHGl ₃₎ 3597, 3333, 1623 and 1597 cm "^'1. MS: m / e 354 (M ⁺ ), 336, 208, I90 and 9I. Analysis: Calculated for C ₂ ^H 3 O 3 ^: O, 77.93; H, 8.53%. Found: . G, 77.95? H, 8.31 %.

¹ - (2 - (, 5-ghe nyl alcohol

(241 mg, 90%), m.p. 65-70 ⁰ G (pentane) of trans-3/2-benzyloxy- ^z l- (2- (5-phenylpentyloqq7)) phenyl.7-cyclohexanol (O _f 355 S, 0.754 mmol )

PWR: JSj ^ ₁ 1.25 (d, J = 6Hz, side-chain methyl), 4.13 (m, carbolic-nol and side-chain methines), 6.26 (d, J = 2Hz, ArIl), 6 , 26 (dd, J = 8 and 2 Hz, ArII), 6.82 (d, J = 8 Hz, arH) and 7.05 (s, PhII). '

IR: m / e 3597, 3378, 1629 and 1587 cm "" ¹ . MSs m / e. 354 (M ⁺ ), 336, 208, -190 and 9I. , Analysis: Calculated for G ₂ 3 ^H 3O ° 3 ^: >77.93; H, 8.53 % · Found:. C, 77.53? H, 8.40%.

-75- 2 182I4

(0.725 S, 68 %) from 1.36 (3.22 mmol) cis -3- _/ 2~3-benzyloxy-4- (1,1-dimethyloctyl) phenyl-7-cyclohexanol.

Melting point: 100 to 101 ⁰ O (recrystallized from hexane).

PMR: QQQ ₁ 0.82 (m, terminal side chain ethyl), 1.22 (s, gem. Dimethyl), 2.90 (m, benzylmethine), 3.12 (bs, OH), 3.70 (in, carbinol methine ), 6.62 (d, J = 2 Hz, ArH), 6.75 (dd, J = 8 and 2 Hz, ArH) and 7.00 (d, J = 8 Hz, ArH). IR: (GHCl3) 3571, 3333, 1626 and 1582 cm ^-1 , * MS: ra / e 332 (M ⁺ ), 314, 233 and 215.

Analysis: Calculated for 022 ^Η 36 ° 2 ^{: C>} ^ * ^ ⁶ '^{H> 1o} »9 ² ^ * Found: G, 79.85; H, 11.03 %.

trans ~ 3- ^ 4 "- (1 j / 1-dimethyl octyl) -2-h ^ droxy_phenyl 7cy_clohexanol (O, 195) g, 100 %) as an oil of 246 mg (0.582 mmol) trans-3- / 2 "-benzyloxy-4α (1,1-dimethyloctyl) phenyl / cyclohexanol. Melting point: 94-95 ⁰ G (from petroleum ether)

fps / yes

Hffi: ODE ° ^'82 ^ ^{m> "beriIlinales} side chain methyl), 1.24

GDGl '^> y,

(s, according to dimethyl), 3.28 (m, benzylmethine), 4.20 (m, carbinolmethine and OH), 6.83 (dd, J = 8 and 2 Hz, ArH), 6.83 (d, J = 2 Hz, ArII) and 7.10 (d, J = 8 Hz, ArH). IR: (CHGl ₃ ), 3650, 3436, 1639 and 1582 cm ^-1 . MS: m / e 332 (M ⁺ ), 314, 233 and 215.

Analysis: Calculated for C ₂₂ H ^ ₆ O ₂ : G »79.46; H, 10.92%. Found: C, 79.34; H, 10.55 %.

(3.99 s, 77%)

of cis -3- (2-benzyloxy-4-t-butylphenyl) cyclohexanol (7.1 g, 0.021 mol)

Melting point: I77 to 178 ⁰ C (from isopropyl ether).

PMR: "p, 1.23 Cs, t-butyl), 2.88 (m, benzylmethine), 3.55

2 1 821 4

(m, carbinolinethine), 6.75 (m, two ArIi), and 6.92 (d, J 8Hz, ArH).

IR (KB _r) 3484, 3268, 1634 and 1592 cm ^"1. MS: m / e 248 (M ^+), 233, 230, 215, 187, 176, 173 and 161. Analysis: Calculated for C ₁₆ H ₂₅ O ₂ : G, 77.37; H, 9.74%. Found: C, 77.00, H, 9.54 %.

(0.725 S, 99 % ') of trans-3- (2-benzyloxy-4-t-butylphenyl)

cyclohexanol (1.25 S, 2.96 mmol). Melting point: I36 to 137 ⁰ O (from isopropyl ether).

PIvIR: ^ _1, 1.27 (s, t -butyl), 3.35 (m, benzyimethine), 4.32 (ra, GaSbinolmethin), 6.95 (d, J = 2Hz, ArH), 6.96 (dd, J = 8 and 2 Hz, ArH) and 7.15 (d, J = 8 Hz, ArH). . IR: (CHGl ₃₎ 3623, 3401, 1626 and 1575 cm ^"1 MS: m / e 248 (M ^+), 233, 230, 215, 187 and 173. Analysis: Calculated for ö ₁₆ H _{2Z |} 0 _2: G, 77.37; H, 9.74%. Found: C, 77.34, H, 9.49 %,

(1 _x 1-whine of Iprop2l) - 2hydro: <2 I, 2'l, 7c2clohcxanol * (1.45 g, 32%) of cis-3 / 2V-benzyloxy-4- (1,1-dimethylpropyl) phenyl] -7cyclohexanol (6.1 g, 0.0173 mol). Melting point: 166 to 167 ⁰ G (from isopropyl ether).

PMR: QQQi DMSO-D ° ^'65 ^ * ~ ^{J 7 HZ} terminal} methyl),

? ⁶

QQQi -DMSO-D ' * ^} y

1.20 (s _s gem? Dimethy ⁶ l), 2.91 O, Benzylmethin), 3.62 (m, Garbinolmethin), 6.75 (m, two ArH), 7.02 (d, J = 8 Hz , ArH)

and 7, ^ (s, OH).

IR: (KBr) 3509, 3279, 1629 and 1592 a " ¹ MS: m / e (M ⁺ ), 247, 244, 233 and 215.

(0.50 s, 68 %) of trans-3- _i / 2 "-benzyloxy-4- (1,1-dimethylpropene)

-7? - 2 1S2! 4

pyl) phenyl 7-cyclohexanoL (1.00 g, 2.84 mmol). Melting point: 124 to 125 ⁰ G (from isopropyl ether).

rnpffo

BEAR: Q ^ q ₁ Ο ,, '.'? (t, J = 7Hz, terminal methyl), 1.23 (according to dimethyl) j 3.30 (m, benzylmethine), 4.05 (m, carbinolmethine), 6.76 (m, two ArH) are 6 , 93 (d, J = 8 Hz, ArH). IR: (OHGl ₃ ) '3636, 3413, 1639 and 1585 cm ^-1 . MS: m / e 262 (M ⁺ ), 247, 244, 233 and 215.

Analysis: Calculated for G ₁₇ H ₂₆ O ₂ : C, 77.82j H, 9.99 %. Found: 0, 77> ^ \ Η, 9,87%.

ο is-3- / 4 * -Q, 1-dimethyl butyl-hydroxyphenyl / cyclohexanol (1.9S, 74%) of cis-3/2-benzyloxy-4-4 (1,1-dimethylbutyl) -phenyl / cyclohexanol (3.39 S, 9.26 mmol). Melting point: I38 to 139 ⁰ G (from Pontan).

PIfR: Q ^ ₁ 0.82 (m, terminal methyl), 1.25 (s, according to dimethyl), ^ 2.90 (m, benzylmethine), 3.78 (m, garbinolmethine), 6.8 (m , ArH) and 7.11 (d, J = 8 Hz, ArH). IR: (IiBr) 3509, 3279, 1629 and 1592 cm ^-1 . MS: m / e 276 (M ⁺ ), 261, 258, 233 and 215.

(0.45 g, 87%) as an oil from trans-3 -. / 2 "-Benzyloxy- 4- (1,1 ~ dimethylbutyl) phenyl] _i 7cyclohexanol (0.700 g, 1.91 mmol).

PMR: (JQGl ^{0> 8} ° ^ ^m »^ ¹ " ¹¹¹¹ - ¹¹³ - ³ - ⁶⁸ methyl), 1,22 (s, acc.

Dimethyl), ^ 3.25 (m, benzylmethine) 4.22 (m, garbinolmethine), 6.81 (d, J - 2Hz, ArH), 6.81 (dd, J = 8 and 2Hz, ArH). and 7.06 (d, J = 8 Hz, ArH),

IR: (CHOl ₃ ) 3636, 3390, 1629 and 1575 cm ^-1 .

MS: m / e 276 (M ⁺ ), 261, 258, 233 and 215.

trans-3/5 ~ (, 1 ^ 1 -

(6.26 mg, 78%) of trans-3 _L / 2 "-benzyl

-ye- 2 10214

oxy-4- (1,1-dimethyl thyheptyl) phenyl _> 7-cis-'4 -. (2-propenyl) cyclohexanol (ί, Ο s, 2.23 mmol)

Melting point: 92 to 94 ⁰ O.

TPt ⁰ I

PMR: Q ^ q ₁ 0.85 (m, terminal methyl), 1.25 (s, acc.

Dimethyl), 3.05 (m, benzyl line thin), 4.22 (m, carbinol methine) 6.55-6.9 (m, ArH) and 7.01 (d, J = B Hz, ArH).

IR: (CHCl ₃₎ 3623, 3390, 1629 and 1578 cm.

Analysis: Calculated for C ₂₄ H ^ ₀ O ₂ : C, 79.94 »H, 11.18%.

Found: C, 80.10; H, 10.89 % ·

(550 mg, 74%) of cis-3/2-benzyloxy-4-

(1, 1-Diynesylheptyl) phenyl / -trans-4- (2-propenyl) cyclohexanol (930mg, 2.07mmol)

Melting point: 126 ^° C. (from pentane). IR: (CHCl ₃ ) 3597, 3390, 1629 and 1575 cm ^-1 . MS: m / e 360 (M ⁺ ) 345, 34-2, 275 and 257.

rpi ,? σ

PMR: QJ ₅ Q ₁ 0.82 (m, terminal methyls), 1.27 (s, acc.

Dimethyl), ^ 2.65 (m, benzylmethine), 3.75 (m, carbinolmethine)

6.75 (m, ArH) and 7.07 (d, J = 8 Hz, ArII).

Analysis: Calculated for O ₂₄ H ₄₀ O _2: C, 79.94; H, 11.18 %.

Found: C, 79.85; H, 10.95%.

(322mg, 80 %) of cis-3/2-benzyloxy-4- (1,1-dime-thyl-1-phenyl) -7,7-trans-4- (2-butenyl) cyclohexanol (500mg, 8mmol )

Climax point: I3I ⁰ C (from pentane). IR: (CHCl ₃ ) 3636, 3356, 1629 and 1587 cm ^-1 . MS. m / e 37 ^ (M ⁺ ), 356, 302, 289, 272, 271, 257, 247, 233, 217, 187 and 161.

PMR: JJJq ₁ 0.8 (m, terminal methyl), 1.28 (s, according to

-re- 218214

methyl ·), 2.67 (m, benzylmethine), 3.70 (m, garbinolmethine), 6.69 (d, J = 2Hz, ArH), 6.82 (dd, J = 8 and 2Hz, ArH ) and 7.07 (d, J = 8 Hz, ArH).

trans-4-PentyJ.-cis-3- ^ f- (1 _Z 1 -dime thy lheg

(225 mg, 76%) of cis-3-Z2-benzyloxy-4- (1,1-dimethylhep-.

tyl) pheryl J7 trans-4- (2-pentenyl cyclohexanol) (363mg, 0.762mmol).

Melting point: '135 to 136 ⁰ G.

PMR: ^ ₁ 0.8 '(m, terminal methyls), 1.23 (s, according to dimethyl), ^ 2.65 (m, benzylraethine), 3.75 (πι, - Caicbinolniethin), 4.88 (s, / OH), 6.7.8 (m, ArH) and 7.02 (d, J = 8 Hz, ArH).

(2.5 g, 60%) of cis-3/2-benzyloxy-4- (1,1-dimethylpentyl) -phenyl-cyclohexanol (3i5 g, 0.014 ^ 1 mol), m.p .: 112 to 113 ⁰ O. (from pentane, isopropyl ether), IR: (GHCl ₃₎ 3636, 3390, 1631 and 1592 cm "^'1.

MS: m / e 290 (M ⁺ ), 272, 233 and 215.

P &ffi; oiioL ° ^'80 ^ ^{m> terniinales} methyl), 1.20 (s, gem. dimethyl), 2, fO (m, benzylmethylene), 3.61 (m, Carbinolmethin) and 6.4 7.1 (m, arii ).

Analysis: Calcd. For G ₁₉ H ₃₀ O ₂ : C, 78.57; H, 10.41%. , Found: C, 78.76; H ₁ 10.11 %.

(385 mg, 78%) of trans-3 - ^ - (benzyloxy-4- (1,1-dimethylpentyl ·) · -phenyl7cycl ohexanol · (640 mg, 1.68 rnlviol) -. Melting point: 114 to II5 ⁰ G (from pentane) IR: (CHGl ₃ ) 3636, 3390, I63I and 1577 cm ^-1 . IvIS: m / e 290 (M ⁺ ), 272, 233 and 215.

18214

PM: IjJj) O ₁ 0.80 (m, terminal it methyl), 1.27 (s, according to dimethyl), ^ 3,30 (m, benzylmethine), 4,28 (m, garbinolmethine), 4,72 (bs, OH), 6.81 (dd, J = 8 and 2 Hz, ArIi), 6.81 (d, J = 2 Hz, ArH) and 7.03 (d, J = 8 Hz, ArH), Analysis: Calculated for O ₁ QHo ₀ O ₂ : G, 78.57; H, 10.41 %. Found: G, 78.38} H, 10.10 %.

, I-dimethylhexyl) -2-hydroxyphenylcyclohexanol · (2.3S, 99%) of cis-3- ^ 2 "-benzyloxy-4- (1,1-dimethylhexyl) phenyl-7-cyclohexanol (3.00 g, 7.61 mmol ). melting point: 98 to 10O ⁰ G. (pentane) IR:. (GHGl ₃₎ 3636, 3367, 1626 and 1587 cm ^'1. IiS: m / e 304 (M ⁺ ), 286, 233 and 215.

PMR: Qi) Cl ° ^»82 ^ ^m> teniiinales-methyl), 1.20 (s, gem dimethyl) · 2.92 (m, Benzylmethin), 3.76 (m, Carbinolmethin) and 6.65 -. 7.4 (m, ArH).

Analysis: Calculated for 0 ₂ 0 ^Η 32 ° 2 ^{! G} »'^ ⁸ » ⁸ 9 » ^H » ΊΟ, 59 %. Found: G, 78.57; H, 10.46 %,

trans ~ 3 - / ^ (1 ^ i-Di ^^ hylhexyl ^ -S-hydrox ^ pheny! ^ cyclohexanol (440 mg, 86 %) of trans-3/2-benzyloxy-4- (1,1- dimethylhexyl) phenyl7cyclohexanol (660 mg, 1.68 mlviol). melting point: 113-114 ⁰ G (pentane) IR:.. (OHGl ₃₎ 3636, 3390, 1631, 1616 and 1580 cm ^"1 MS / m / e 304 ( M ⁺ ), 286, 233 and 215. HRMS: 304.2419 ()

(4.0 g, 100%) of cis -3- / 2-benzyloxy-4- (1,1-dimethylnonyl) phenyl / cyclohexanol (5.0 g, 1.15 mmol). Melting point: 82 to 83 ⁰ G (pentane).

- si -. 2 18214

IR: (CHOl ₃ ) 3650, 3390, 1637 and 1597 cm ^-1 . FiS: m / e 346 (M ⁺ ), 328, 233 and 215.

Analysis: Calculated for C ₂₃ Ho ₈ O _2: 0, 79.71; H, 11.05%. Found: 0, 79.71; H, 11.14%.

(7.09mg, 89 %) of trans-3/2 "-benzyloxy-4- (1,1-dimethylnonyl) phenylcyclohexanol (1.00g, 2.29mmol).

Melting point: 69 to 70 ° C, (pentane).

IE: (OHOl ₃ ) 3636, 3413, 1631, 1618 and 1582 cm ^-1 .

MS: ia / e 346 (M ⁺ ), 328, 233 and 215.

PMR: oJjg _L 0.87 (m, terminal methyl), 1.22 (s, according to dimethyl), *> 3.30 "(m, benzylmethine), 4.22 (m, carbinol methine), 4.98 ( bs, OH) and 6.7-7.3 (m, ArH).

Analysis: Calculated for C ₂₃ H ₃₈ O _2: G, 79.71 »H, 11.05%. Found: C, 79.11; H, 10.86%.

2, Yl:) -2-hydroxybenzenecyclohexanol

(2.02 g, 98%) of cis-3/2 "-benzyloxy-4- (1,1-dimethyldecyl) J7-cyclohexanol (2.6 g, 5.78 mmol)

Melting point: 93 to 94 ⁰ O (pentane). IR: (GHOl ₃ ), 3636, 3390, 1629, and 1587 cm ^-1 . MS: m / e 360 (M ⁺ ), 342, 288, .233, and 215.

mp.f σ

PMR: Q ^ o ₁ 0.83 (m, terminal methyl), 1.20 (s, according to dimethyl), ^ 2.85 (m, benzylmethine), 3.75 (m, carbinolmethine), 4.4 ( broad, OH) and 6.4-7.2 (m, ArH). Analysis: Calculated for G ₂ 4 ^H 40 ° 2 ^{: C} »79.9 ^; H, 11.18 %. Found: C, 80.12; H, 11.39 % ·

(130mg, 45 %) of trans-3-Z2-inizyloxy-4- (1 → 1-dimethyldecyl) -phenyl.7cyclohexanol (360mg, 0.80mlol).

2 10214

Melting point: 76 to 77 ^° C.

IR: (GHGl ₃₎ 3636.3425, 1631, 1616 and 1580 cm ^"1

MS: m / e (M ⁺ ), 342, 233 and 215.

Plvffi: ^ ₁ 0.86 (m, ternimal methyl), 1.22 (s, according to dimethyl), ** 3.2 (m, benzylmethine), 4.17 (m, carbinolmethine and OH) and 6.6 - 7.2 (m, ArH).

Analysis: Calcd. For C ^ H ^ O ^ C, 79.94; H, 11.18 %. Found: . C, 80.20; H, 11.27%.

(2.39 g, 85%) of cis-3/2-benzyloxy-4- (1,1-dimethyl

cyl) phenyl-7-cyclohexanol (3.5 g, 7.54 mmol).

Melting point: 85 to 86 ^° C.

IR: (CHGl ₃ ) 3636, 3390, 1634 and 1592 cm ^-1 .

MS: m / e 374 (M ⁺ ), 356, 233 and 215.

TM "-}

BUR: GDOl ° »^ ⁸ ^ ^{m 'termij: iales} methyl), 1.22 (s, gem di methyl), ^ 2.98 (m, Benzylmethin), 3.95 (m, Carbinolmethin), 6.83. (m, ArH) and 7.09 (d, J = 8 Hz, ArH). Analysis: Calculated for G2 ^rH 42 ° 2 ^{: G} > ^8O > ¹ 5 ;. H, 11.30 %. Found: C, 80.11; H, 11.16%. '

(0.793 g, 73%) of cis-3- / 2 "-benzyloxy-4- (1,1-dimethylheptyl) phenyl7cyclooctanol (1.36 g, 3.11 mmol). Melting point: 89-90 ⁰ C (from pentane MS: m / e 346 (M ⁺ ), 328, 261 and 243.

φηιιο

PMR: qiqi °> ⁸ 3 (m, terminal methyl), 1.22 (s, according to Di

methyl), ^ 3.0 (bin, benzylmethine), 3.98 (bm, carbinolmethine), 6.75 (m, ArII), and 7.00 (d, J = 8 Hz, ArH). ₉ Analysis: Calculated for C ₂₃ H ₃₈ O ₂ : C, 79.71? H, 11.05 % · Found: C, 79.90; H, 10.89% _#

-83- 2 18214

(2.62 s, 83%) of trans-3 ~ _/ / 2-benzyloxy-4- (1,1-dimethylheptyl) phenyl7cyclooctanol (4.0 g, 9.17 mmol) · Melting point 76 to 77 ⁰ O ( from pentane). BTiS: m / e 346 (M ⁺ ), 328, 261 and 243.

PMR: Q ^ ₁ 0.83 (m, terminal methyl), 1.24 (s, according to dimethyl), 3.15 (t> m, benzy ^ methine), 4.05 (m, carbinol methine), 6, 78 (m, ArH) and 7.02 (d, J = 8 Hz, ArH), Analysis: Calculated for C ₂ ^H 3 38 ° 2 ^{: G} »79.71; H, 11.05 % * Found: · O, 79.81; H, 10.86%.

Beisgiel_20

^ zZEr " (^ i..1 --Pi ¹¹¹ ^ t hy Iheg tyl) ~ 2-hy dr ogy phenyj.7cyc 1 ohe x-2-e non A mixture of 400 mg (0.988 mmol) 3- / 2- Benzyloxy-4- (1,1-dimethylheptyl) phenyl _> 7-cyclohex-2-enone and 20 mg of 5% palladium on charcoal were filtered from a diatomaceous earth for 30 minutes under a hydrogen pressure and the filtrate became a solid The crude material was recrystallised from petroleum ether to give 110 mg (35 %) of the title compound, mp 122-123 ⁰ .

PMR: Qj) Qi °> ⁸² ( ^m > terminal side chain methyl ), 1.30 m

(s, according to dimethyl), 2.19 (dt, J = 6 and 6 Hz, C-5-methylene), 2.52 (t, J = 6 Hz, C-4-methylene), 2.80 ( t, J = 6Hz, C-6-methyl), 6.7-7.4 (m, ArH and Yinylprotbn) and 8.16 (s, phenol), IR: (KBr) 3448, 1634, 1608 and 1565 cm " ¹ .

m / e (M ⁺ ) 299 and 229

Analysis: Calculated for Ö21 ^H 30 ° 2 ^{i G> 80} ^ i ^H >9> 62%. Found: · C, 80, 23; H, 9.46%.

Beisgiel__21

218214

To a solution of O ⁰ O having 7.0 g (33.0 mmol) of 3- (2,4-dihydroxy) -cyclohexanone in 100 ml of methanol and 15 ml of trimethyl orthoformate was added 10 drops of concentrated sulfuric acid then stirred for three hours without cooling, so that the temperature could rise to room temperature, and then quenched by the addition of an excess of solid sodium bicarbonate.The reaction mixture was evaporated under reduced pressure and the residue dissolved in 200 ml of water / 250 ml of ether saturated Natriumhydrogenearbοnat was ether extract once with 150 ml, dried over magnesium sulfate, and evaporated. the oily residue was crystallized from ether-pentane to give 5-, 74- g (77%) of the title compound eibem melting point of 129 "to 130 ⁰ g ,

rrm / ro

PMR: QQQ ₁ 1.4-2.5 (m, methylenes), 3.20 (in, methine), ³

QQQ ₁ ,,, y),,,,, 3.50 (s, OMe ³ ), 5.58 (s, OH) 6.38 (dd, J = 8 and 2 Hz, ArH), 6.43 (s , overlapping 6.38) and 6.87 (d, J = 8 Hz). IR: (KBr) 3289, 1629, 1613 and 1597 cm "" ¹ _β MS: 220 (M ⁺ ), 205 »203, 188, 177, 161 and 136. Analysis: Calculated for G ^^ E ^^ Oy. 0, 70.89; H, 7.32 %. Found: 0, 70.79; H, 7.34%.

By repeating this procedure, but using triethyl, tri-n-propyl or tri-n-butyl orthoformate instead of trimethyl orthoformate and ethyl, n-propyl or n-butyl alcohol instead of methanol, the corresponding ethyl, n-propyl are formed and n-butyl ketals.

ketal

-es- 2 102t 4

A mixture of 5.03 S (22.8 mmol) of 3- (2,4-pihydro-plenyl) cyclohexanone methyl ketal, 10.1 g (73.2 mmol) of anhydrous potassium carbonate and 6.12 g (26.8 mmol) of 4 -Phenylbutylmethansulfonat in 25 ml of N,! ^ - dimethylformamide was maintained for 4 hours at 85 to 100 ⁰ O. The reaction mixture was cooled and 200 ml of Yiasser / 200 ml of ether were added. The ether extract was washed twice with 200 ml of water, dried over magnesium sulfate and evaporated to an oil. The oil was purified by column chromatography on 400 g silica gel eluting with a 2: 1 mixture of pentane and ether to give 7.4 g (92 %) of the title compound as an oil.

PMR: Q ^ ₁ 2.63 (m, benzylmethylene), 3.33 (s, OCH ₃ ), 3.85 (bt, J = 6% z, OCH ₂ ), 6.42 (dd, J = 8 and 2 Hz, ArH), 6.50 (bs, overlaps 6.42, ArH), 6.92 (d, J = 8 Hz, ArII) and 7.30 (s, PhH).

IR: (CHCl ₃ I, 1623 and 1590 cm ^-1) FiS: m / e 352 (M ⁺ ) and 9I

Analysis: Calculated for C ₂₃ H ₂₈ Oo: C, 78.37; H, 8.01 %, Found: C, 78.34; H, 8.07 % ·

The following compounds were prepared in a similar manner but using the appropriate mesylate derivative instead of 4-phenylbutyl methanesulfonate.

(6.13 g, 75 %) in the form of an oil of 5.7 g (25.9 mmol) of 3- (2,4-dihydorxyphenyl) cyclohexanone methyl ketal and (2-heptyl)

methanesulfonate (6.2 g, 32.3.ψΜο1). , ·

IR: (CHCl ₃ ) 1637 and 1600 cm " ¹ ,

FiS: m / e 318 (M ⁺ ), 286, 274, 220, 204 and 178.

^PMR: CDCl ° '9 ° ( ^m > methyl), 1.18 (d, J = 7 Hz, methyl),

2 1821

3.03 (m, methine), 3.35 (s, MeO), 4.14 (m, methine), 6.35 (m, ArH) and 6.68 (d, J = 8Hz, ArH).

-4- (2-Oxytoxy) -glyl-1-hexanone-1-hexanone, as an oil (5.03S, 58 %) of 3- (2,4-Mhydroxyphenyl) cyclohexanone methyl ketal (5.7 g , 25.9 mmol) and (2-octyl) methanesulfonate (7.3 S, 35.1 mmol). IR: (CH 2 Cl 2) 1639 and 1600 cm ^-1 .

ES: .m / e 332 (M ^T ), 300, 289, 272 and 220.

BEAR: Q ¹ Q ¹ Q ₁ 0.87 (m, methyl), 3.09 (m, methine), 3.36

Cs ₁ OMe), 3 4.20 (m, methyl), 6.30 (m, ArII) and 6.80 (d, J a 8 Hz, ArII).

(5.23%, 59%) in the form of an oil of 3- (2,4-dihydroxypropylcyclohexanone methyl ketal (5.7 g, 25.9 mmol) and (2-naphthyl)

nyl), ethanesulfonate (7> 9S, 35.5 mmol).

IRi (CHGl ₃ ) 1634 and 1590 cm ^-1 .

FiS; m / e 346 (M ⁺ ), 314, 220, 188 and 161.

PMRi ^ ₁ 0.87 (m, methyl), 3.10 (m, methine), 3.39 (s, OMe), 4 ^ 22 (m, methine), 6.36 (m, ArIi) and 6, 80 (d, J = 8 Hz, ArII).

ketal

in the form of an oil (5.1 g, 56%) of 3- (2,4-dihydroxyphenyl) cyclohexanone methyl ketal {^^ 7 g, 25.9 mmol) and 2 ~ (4 ~

Phenylbutyl) methynesulfonate (8.0 g, 35, OmMoI),

IR; (CHCl ₃ ) 1639 and 1603 cm ^-1 .

MS: m / e 352 (M ⁺ ), 320, 220 and 188. ITOiC!

HCR; Q ^ g ₁ 1.29 (d, J = 6 Hz, methyl), 3.07 (m, kethine),

- 87- 2 102ί 4

3.38 (s, OMe), 4.26 (m, methine), 6.30 (m, ArH), 6.80 (d, J = 9Hz, ArH), and 7.16 (s, PH).

(5.3 S, 54-%) in the form of an oil of 3- (2,4-dihydroxyphenyl) cyclohexanone methyl ketal (5.7 S, 25.9 mmol) and 2- (6-phenyl)

hexyl) methanesulfonate (9.0 g, 35.5 mmol).

IE: (CHOl ₃ ) 1634 and 1597 cm ^-1 .

MSt m / e 380,2342 (M ⁺ , O ₂₅ H ₃₂ O ₃ ), ^22ο » ¹ Ο ⁸⁸ > 188,0986 and

177.0550.

^PMRi CDOl 1 » ²⁶ ( ^d » J = ^{6 Hz} > methyl), 3.10 (m, methine), 3.40 (s, OMi?), 4.22 (m, methine), 6.30 (m, ArH), 6.83 (d, J s 9 Hz, ArH) and 7.18 (s, Ph).

A mixture of 6 _} 8 g (19 $ 3 meIol) of 3- ^ 2-hydroxy-4 ~ (4-phenylbutyloxy) phenyl-7-cyclohexanone methyl ketal, 100 ml of 2N hydroiodic acid and 60 ml of dioxane was added for 1 hour. cooked under reflux. The reaction mixture was cooled and added to 300 ml of ether / 500 ml of saturated sodium chloride. The ether extract was washed once with 500 ml of saturated sodium chloride and 500 ml of saturated sodium bicarbonate, dried over magnesium sulfate and evaporated to an oil. The oil was purified by column chromatography to 400 g. Purified silica gel eluting with a 1: 1 mixture of ether and cyclohexane to give 6.4 g (98 %) of the title compound in the form of an oil.

· PIvlR. ^ ₁ 2.69 (m, benzylmethylene), 3.90 (bt, J = 6Hz, -00H ₂ -), ³ 6 _$ 25-6.5 (m, ArH), 6.32 (d, J = 8 Hz, ArII) and 7.20 (s, PhH).

IB2ii

IR: (OHGl ₃ ) 3571, 3333, 17.18 (weak), 1626 and 1595 cm ^-1 . MS: m / e 388- (M ⁺ ), 320, 310, 295, 268 and 91.

The following compounds were prepared in the same manner from the appropriate ketals of Example 22:

(4.7 g, 82%), in the form of an oil of 6.0 g (18.8 mmol) of the corresponding methyl ketal.

IR: (GHGl ₃ ) 3636, 3390, 1724 (weak), 1639 and 1600 cm ^-1 . MS: m / e 304 (M ⁺ ), 206, 188, I7I, 163 and 137.

PMR: ^ ₁ 0.82 (in, methyl), 1.25 (d, J = 6 Hz, methyl), 4.15. (m, side chain methine), 6.35 (dd, J = 8 and 2 Hz, ArH), 6.35 (d, J = 2 Hz, ArH) and 6.81 (d, J = 8 Hz, ArH ).

(4.1 g, 85%) in the form of an oil of 5.0 g (15.0 mmol) of the corresponding methyl ketal.

IR: (CHGl ₃ ) 3636, 3378, 1721 (weak), I63I and 1595 cm ^-1 . MS: m / e 3I8 (M ⁺ ), 206, 188, 178 and 161.

HvER: Ίχ ^ ι ° » ⁸ ^ ( ^m > methyl), 4.20 (m, side chain methine), 6.39 (dd, A 8 and 2 Hz, ArH), 6.39 (d, J = 2 Hz, ArH) and 6.83 (d, J = 8 Hz, ArH).

(4.35 g, 89%), in the form of an oil of 5.1 g (14.7 mmol) of the corresponding methyl ketal.

IRs (GHGl ₃₎ 3584, 3367, 1709 (weak), 1626 and 1587 cm ^"1 * MS: m / e 332 (M ^+), 206, 187 and 171,

BLE: ™ _Ί 0.85 (m, methyl), 4.26 (m, side chain _methine ),

Q ^ Q ₁ ,, y,

6.39 (dd, J ³ = 9 and 2 Hz, ArH), 6.39 (d, J = 2 Hz, ArH) and 6.84 (d, J = 8 Hz, ArH).

- 89 - 2 1 S21 4

² z

(3.8 g, 79%) from 5.0 g (14.2 mmol) of the corresponding methyl ketal in the form of an oil.

IR: (OHCl ₃ ) 3636, 3425, 1724 (weak), 1637 and 1600 cm ^-1 MS: m / e 338 (M ⁺ ), 206, 188, 132, 117 and 9I PFiE: ^ ¹ Q ₁ 1 , 29 and 1.27 (d, J = 6Hz, methyl), 3.02 (m, methine in ^ hemicetal form), 3.73 and 4.22 (m, methine), 6.30 (dd, J = 8 and 2 Hz, ArH), 6.30 (d, J = 2 Hz, ArH), 6.81 (d, J = 2 Hz, ArH) and 7.18 (s, Ph).

- (6-phenylhexyloxy) z2-hydroxypheny_1.7cyclohexanone (4.45 g, 89 %) as an oil from 5.2 g (13.6 mmol) of the corresponding methyl ketal.

IR: (CHOl ₃ ) 3636, 3390, 1718, 1637 and 1600 cm ^-1 . MSs m / e 366 (M ⁺ ), 206, 188 and 9I.

EMRs.- Q ^ q ₁ 1.25 (d, J = 6 Hz, methyl), 3.07 (m, methine), 4.19 (m, Me ³ thin), 6.32 (dd, J = 9 and 2Hz, ArH), 6.32 (d, Jβ2Hz, ArH), 6.73 (d, J = 9Hz, ArH) and 7.14 (s, Ph).

(Yyy) p2.72; and the trans isomer

To a solution of -18 ⁰ C of 4.8 g (14.2 mmol) of 3- / 2-hydroxy-4- (4-phenylbutyloxy) phenyl ^ cyclohexanone in 25 ml of methanol was 0.539 S (14.2 mmol) Sodium borohydride given. The reaction mixture was stirred for 40 minutes, then added to 250 mL of saturated matrium chloride / 250 mL of ether. The ether extract was washed once with 150 ml of saturated sodium chloride, dried over magnesium sulfate and evaporated to an oil. The oil was purified by column chromatography on 400 g silica gel eluting with a 2.5: 1 mixture of dichloromethane to ether to give 3.37 g

2! 8214

(70 %) of the cis isomer crystallized from cyclohexane, u $ d 0.68 g (14 %) of the trans isomer, crystallized from cyclohexane, and 0.69 g (14 %) of mixed material.

Melting point: 79 to 80 ⁰ O.

^PMRi ODGl ^{2> 7} ° ^ ^m ' ^Be nzylmethylene), 3.26 (m, benzylmethine),

GDGL

3.93 (bt, B = 6 Hz, -OGH ₂ -), 4.28 (m, garbinolmethine, with D ₂ O 4,25, M, garbinolmethine), 6,42 (dd, J = 8 and 2 Hz , ArH) 6.45 (d, J = 2 Hz, ArH), 7.03 (d, J = 8 Hz, ArH) and 7.22 (s, PhH). ν

IR: (GHGl ₃₎ 3610, 3333, 1631 and 1603 cm ^"1. MS: m / e 340 (M ^+), 322, I90 and 9I.

Analysis: Calculated. For 0 ₂ 2 ^H 28 ° 3 ^ic »77.61; H, 8.29 % · Found: G, 77.46; H, 8.25%.

trans-isomer £ Melting point: 112 to 114 ⁰ C.

PLiR: Q ^ ¹ Q ₁ 2.68 (m, benzylmethylene), 3.80 (m, OH, - ₂ , Carbinolmet- ^ hin, with D ₂ O 3.63, m "C arb inolme thin and 3.90 , bt, J = 6 Hz, -OGH ₂ -), 6.32 (bs, overlaps 6.40), 6.40 (dd, 'J = 8 and 2 Hz, ArH), 7.00 (d, J = 8 Hz, ArH) and 7.20 (s, PM).

IR: (CHGIo) 3610, 3390, 1631 and 1595 cm ^-1 . MS: m / e 340 (M ⁺ ), 322, I90 and 9I.

Analysis: Calculated for C ₂ 2 ^H 28 ° 3 ^: °>77.61; H, 8.29 %, Found: C, 77.40; .H, 8.31 %.

In the same way, the following compounds were prepared:

and the ££ ans isoin in the form of oils of 3- / 4 ^. (2-heptyloxy) -2-hydroxyphenyl-7-cyclohexanone (5.2 g, 13.6 mmol). In the home

18214

Following elution of silica gel, 854 mg (36 %) of the ice-3 and 107 mg (3 %) of the trans ~ 3 isomer were recovered.

IR: (CHOl ₃ ) 3597, 3333, 1629 and 1600 cm ^-1 . MS: m / e 306 (M ⁺ ), 208, I90, 173 and 162., PMR: ™ q _X 0.82 (m, methyl) , 2.8 (m, benzylmethine), 3.7 (m, carbinoimethine and OH), 4.1 (m, methine), 6.38 (m, ArH) and 6.93 (d, J = 8 Hz, Ar H)

 tran.s_ £.

MS: m / e 306 (M ⁺ ), 208 and I90.

HlR: Q ^ ₁ o, 82 (m, methyl), 3.25 (m, benzylmethine), 4.3 (m, carbinoethine and OH), 6.33 (m, ArH) and 6.94 (d, J = 8 Hz, ArH).

n.sub.10 cyanogen octanol and the trans isomer of 3-Z4- (2-octyloxy) -2-hydroxyphenyl-7-cyclohexanone (2-92 g, 9.18 mmol). In the order of the silica gel blotting, 1.53 g (54%) of the cis-3 and 0.57 g (19 %) of the trans-3 isomer were recovered.

.IR: (OHCl ₃ ) 3663, 3390, I637 and 1608 cm ^-1 . MS: 'm / e 320 (M ⁺ ), 319, 208 and I90.

PMR: ™ q _L 0.83 (m, methyl), 2.81 (m, benzylmethine), 3.8 (m, carbinol methine), 4.1 (m, side chain methine and OH), 6.35 (m, ArH ) and 6.96 (d, J = 8 Hz, ArH).

transr ...

IR: (CHCIo) 3636, 3390, 1634 and 1595 cm ^-1 .

MS: m / e 320 (M ⁺ ), 235, 208, I90 and 173.

PMR: ^ ¹ Q ₁ 0.82 (m, methyl), 3.25 (m, benzylmethine, 4.1 4.9 (m, oaroinol and side chain methine, and OH) 6.35 (m, ArIl) and 6 , 96 (d, J = 8 Hz, ArH).

218214

ice cream 3ζ

and the trans isomer of. 3 - / ^ (2-Nonylo: ^) - 2-Hydroxyphenyl-7-cyclohexanone (31.5 S, 19.48 mmol). In order of elution with silica gel, 2.11 g, (67%) of the cis-3- and 0.32 g (10 %) of the trans-3 isomer were recovered in the form of oils.

IRj (CHGl ₃ ) 3663, 3390, 1639 and 1610 cm ^-1 .

FiS: m / e 334 (M ⁺ ), 316, 208 and I90.

PMR: QpQ ₁ 0.88 (m, methyl), 2.85 (m, benzylmethine), 3.5 4.1 (m, urinary methine) and OH), 4.22 (m, side chain methine), 6.38 ( m, ArH) and 6.97 (d, J = 8 Hz, ArH).

IR: (GHOl ₃ ) 3636, 34-13, 1637 and 1592 cm ^-1 MS: m / e 334 (M ⁺ ), 316, 208, 206 and I90.

PMR: ™ q _X 0.88 (m, methyl), 3.23 (m, benzylmethine), 3.9-4.6 (m, carboxy-binol and side-chain methine and OH), 6.36 (m, ArH) and 6.96 (d, J = 8 Hz, ArH).

and the trans isomer of 3 - / ^ - (2- (4-phenyl) butyloxy) -2-hydroxyphenyl / cyclohexanone (2.9 g, 8.23 eq / l). In order of elution with silica gel, 1.29 g (44 %) of the cis-3 and 241 mg (8 %) of the trans-3 isomer were recovered.

Melting point: 96 to 105 ⁰ G (from pentane) IR: (CHGl ₃ ) 3636, 3390, 1634 and 1608 cm ^-1 .

m / e 340 (M ⁺ ), 322, 208, I90, 162, 147, 136 and 9I

PMR: Q ¹ ^ ₁ 1.30 (d, J 6Hz, methyl), 3.75 (m, garbinolmethine), 4.2p (m, side chain methine), 6.21 (d, J = 2Hz, ArH) , 6.38 (dd, J = .8 and 2 Hz, ArH), 6.98 (d, J = Hz, ArH) and 7.20 (s, Ph).

-93- 2 18214

Analysis: Calcd. For G ₂₂ H ₂₈ O ₃ : G, 77.81; H, 8.29 % · Found: G, 77.59; H, 8,18%.

trans ^ IR: (CHOI ₃ ) 3623, 3390, 1637 and 1595 cm ^-1 .

m / e 3 ² K) (M ⁺ ), 342, 208, I90, 162, 147, 136 and 9I.

PIvIR: ^ ¹ Q ₁ 1.30 (d, J a-6 Hz, methyl) 3.3 (m, benzylinethyne), 4.23 (in, carbinol and side chain methine), 6.38 (m, ArH), 6.94 (d, J s 8 Hz, ArH) and 7.18 (s, Ph).

and the trans isomer of 3-4- (2- (6-Phenyl) hexyloxy) -2-hydroxyphenyl cyclohexanol (3.3 g, 9.01 mmol). In the order of elution with silica gel, 1.54 g (46 %) of the cis-3 and 274 mg (8 %) of the trans-3 isomer were recovered.

Melting point: 99 to 113 ⁰ G (from pentane).

IR: (OHOl ₃ ) 3636, 33 & 7, I63I and 1592 cm ^-1 .

MS: m / e 368 (M ⁺ ), 350, 208, I90, 162, 147, 136 and 9I.

HiR: Q ^ q ₁ 1.30 (d, J = 6 Hz, methyl), 3.6 (m, carbinol methine), 4.2 ^ (m, side chain methine), 6.37 (m, ArH), 6, 98 (d, J = 8 Hz, ArH) and 7.18 (s, PhH).

Analysis: Calculated for C ₂ 4 ^H 32 ° 3 ^{; G} '78,22; H ₁ 8.75%. Found: G, 78.05 »H, 8, 56%.

IR: (GHGl ₃ ) 3636, 3413, 1634 and 1597 cm ^-1 .

MS: m / e 368 (M ⁺ ), 350, 308, I90, 162, 147, 136 and 9I.

PM: Q ^ ₁ 1.25 (d, J s 6 Hz, methyl), 4.21 (m, garbinool and side-stream methine), 6.37 (m, ArH), 6.95 (d, J = 8 Hz, ArH) and 7.15 (s, PhH).

For £ 25: "

(1 _X 1-Dime thy lheptyl2-2

~ 2 1 821 4

Having a -30 ⁰ O solution of 1.00 g (3.18 mmol) of 3 - ^ / ZiL _(I} 1-dimethylheptyl) -. 2 - were hydro ^ phenyl7-2-cyoi (iihexanon in 60 ml of ether meadow drops 6.3 ml of a 1 M solution of diisobutylaluminum hydride (in toluene). The Reactions- 'mixture was further stirred for 30 minutes at -30 ⁰ C and then added to 1.5 1 water. Dieabgeschreckte solution was washed with three 400 portions of ether were extracted and the combined extracts were washed twice with 125 ml of saturated sodium chloride and dried over magnesium sulfate After evaporation, the reaction mixture was purified by column chromatography on 50 g of Florial eluting with ether to give an oil from pentane yielded 256 mg (25%) of the title product. melting point: 87-88 ⁰ · O.

FiS: m / e 316 (M ⁺ ), 298, 231 and 213.

PMR: QpQ ₁ 0.83 (m, ternimal methyl), 4.37 (m, carbinol

methine), 5 »0 (m, vinyl H), 6.37 (B, 37 (b, OH) and 6.87 ArH).

Analysis: Calculated for C ₂ 1 ^H 32 ° 2: 0, 79.70; H, 10.19%.

Found: 0, 79.68; H, 9.96 %.

Beispiel_26 £

To a -18 ⁰ G solution of 17.5 g (50 mmol) of 3-, A- (1,1-Diinethylheptyl) -2-hydroxyphenyl7-cyclohex-3-enone in 50 ml of methanol, 1.9 g (50 mmol Sodium borohydride was added. The reaction mixture was stirred for 30 minutes and then added to 250 ml of saturated sodium chloride / 250 ml of ether. The Ätherextrakt was .. once with 250 ml of saturated sodium chloride, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on 400 g of silica gel eluting with

-95- 2 1 © 21 4

Purified 50 % ether-pentane to give the title compound. ,

Example: 27

3- ^ 7 ^ (1, 1-Dimethy lheptyl) -2 hy droxyphenyT7c yclohex-2-en-1-oil To a -18 ⁰ O-containing solution of 70.0 g (0.20 mCi) 3- / 3 - (1,1-dimethylheptyl) -2-hydroxyphenyl-7-cyclohex-2-enone in 200 ml of methanol was added 7.6 g (0.20 McI) of sodium borohydride. The reaction mixture was stirred for 30 minutes and then added to 1 liter of saturated sodium chloride. The ether extract was washed once with 500 ml of saturated sodium chloride, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on 500 g of silica gel eluting with 50% ether-pentane to give the title compound.

Similarly, by reduction of the 3 - / ^ - (Z- ¹ VY) -2-hydroxyphenylcycloalk-2-enones of Example 20, compounds were obtained having the formula:

Z-W

wherein X, Rp, Z and YI corresponded to the definition given in this example

Hydrochloric acid. The acidified mixture is extracted with ethyl acetate (2 x 100 ml), the extracts are taken together, washed with brine and dried (MgSO ₄ ). Evaporation under reduced pressure gives the title product as an oil.

-96- 2 1 021 4

Similarly, the other phenol compounds of formula IA-ID according to the invention are converted to their monoacetoxyesters (the phenolic hydroxy group) and converted to the corresponding ester derivatives by substitution of the anhydrides of propionic, butyric and periferic acids.

Example 29;

cyclohexane

To a solution of 2.0 g of 3- / 2-hydroxy-4- (2- (5-phenyl-7-pentyloxy) phenyl) -cyclohexanol in 20 ml of pyridine at 1o C was added 20 ml of acetic anhydride and the mixture was stirred for 18 hours It was then poured onto ice / water and acidified with dilute hydrochloric acid. The product was isolated by extraction with ethyl acetate (2 × 100 ml), and the combined extracts were washed with brine, dried (MgSO 4), and evaporated to recover the Diacetylderivat in the form of an oil.

In the same way, the compounds of formulas IA-ID, wherein B is hydroxy or hydroxymethyl and 3L · hydrogen, were converted to their diacyl derivatives. By replacing the acetic anhydride with propionic, butyric or vinylic anhydrides, the corresponding diacyl derivatives result.

Example ßO;

3. ~ ^ 2 ~ (4 ~ Morpholinobütyrylo3Qy) -4- (1 ₁ 1-dime thy lheptyl) phenyl /

cyclohexanol

Dicyclohexylcarbodiimide (0.227 g, 1.1 mmol) and 4-N-piperidylbiracetic acid hydrochloride (0.222 g, 1.0 mmol) are added to a solution of 3- / 2-hydroxy-4- (1,1-dimethylhephenyl) phenyl) cyclohexanone ( 0.300 g, 1.0 mmol) in methylene chloride (25 ml)

-97- -218214

at room temperature. The mixture is stirred for 18 hours, then cooled to ⁰ ° and filtered. Evaporation of the filtrate yields the title product in the form of its hydrochloride salt. »

Similarly, the reactant of this example and the remaining phenolic compounds of this invention are converted to the basic esters of the phenolic hydroxy group by reaction with the appropriate basic acid reagent. In this case, esters in which the R 1 component has the following values are prepared: -00GH ₂ WH ₂

₂₂₄₉₂ -CO (CH ₂ ) -N- (methyl) piperazino-COO (CHO) ₂ (OH ₂ ) ₂ -piperidino-00 (OH ₂ ) ₃ N (O ₂ H ₂ ) ₂ -O-OH (GHo) (OH ₂ ) ₂ -morpholino-Co (CH ₂ ) o -pyrrolo -GO (CH ₂ ) -pyrrolidino-O-OH-g-pyrrolo-CO (CHP) ^ - piperidino ()

_237- C0 (CH ₂ ) ₂ -N-butylpiperazino

Careful neutralization of the hydrochloride salts gives free basic esters which can be converted to other acid addition salts. Thus, the hydrobromide, sulfate, acetate, manate, citrate, glycolate, gluconate, succinate, sulfosaiicylate, and tartrate salts are prepared.

-98- 2 t 821 4

2 ^ _Λ ^^^ gny 17-1-me th ^ lencyc

lohexan '"·

To a 50% sodium hydride / mineral oil mixture (2, 28 g, 48 nmol) (3 χ 25 ml portions of pentane washed), 90 ml of dry Dimethylsulfocid given, and the mixture is long 3/4 hour at 7O ⁰ O held. 17.79 g (51 mmol) of methyltriphenylphosphonium bromide are then added in one portion. The yellow solution is stirred at 25 ° 0 for 30 minutes, and then (6.3 nmol) of 3-Z ² "~ acetoxy-4- (1,1-dimethylheptyl) dissolved phenyl7cyclo-hexanone at once 2.26 g in 90 ml of dimethylsulfoxide, and the mixture is kept at 63-65 for 11/2 hours, the reaction mixture is then poured into 150 ml of ice-water / 25 g NaHGO 4 and extracted with 3 × 50 ml of ether, the combined extracts are extracted dried over MgSO 4, decolorized with charcoal, and filtered through a pad of silica gel to yield the colorless oil which is chromatographed on silica gel (eluted with solvent-cyclohexane) First, a non-polar contaminant is eluted, then The polarity of the solvent is increased to ether / cyclohexane (1:10) to give the title compound as a colorless oil.

In the same way, the cycloalkanone and cycloalkene-on compounds described herein are converted to their corresponding methylene derivatives.

A solution dissolved in 25 ml of dry tetrahydrofuran

- 99 g WZ- * "" '---

21S214

Cyclohexane (3 mmol) is cooled to ⁰ ° C. in an ice / water bath. Borane / tetrahydrofuran complex (4.5 mL, 4.5 L solution) is added and the colorless solution is stirred overnight at ambient temperature (18 hours). The mixture is cooled in ice and 8 ml of water are added to decompose the excess reactants. It is stirred for 15 minutes, then the addition of 3 ml (9 mmol) of 3N sodium acetate followed by 3 ml of 30% hydrogen peroxide. It is stirred for 15 minutes at ⁰ ° C, then allowed to warm to room temperature and stirred overnight (24 hours). The reaction mixture is poured onto 100 ml of ice / water and then extracted with 3 x 50 ml of ether. The combined ether extracts are washed with sodium sulfite until negative on the starch KI test, dried over MgSO4, and evaporated to dryness to give a light yellow oil which is applied to 50 g of silica gel (eluting with solvent). Cyclohexane / ether 3: 1) to give the product as a colorless foam.

Similarly, the remaining cycloalkanones and cycloalkanones of Example y are converted to the corresponding hydroxymethyl derivatives.

Catalytic hydrogenation of the above compounds by the procedure of Example 2 gives the corresponding phenolic compounds.

p_ropeny_l) cyclohe ± anol

~ 2 1 821 4;

A solution of trans-3- ^ 2 -benzyloxy-4- (1,1-dimethylheptyl / phenyl-T-cis-4- (2-propenyl cyclohexanol (900 mg, 2.01 mmol) and 2.74 ml, 2.2 M n-butyllithium (in hexane) in ether (3 mL) was stirred for 2 days at room temperature, a second 2.0 mmol portion of n-butyllithium added, and the reaction stirred for a further 2 days The reaction mixture was added to saturated ammonium chloride (250 ml) and the mixture extracted with ether The ether extract was dried over magnesium sulfate and evaporated The residue was purified by column chromatography on 20 g of silica gel eluting with 50 % ether-pentane to give 621 mg (88%) of the title compound. melting point: 85 to 9I ⁰ O

IKi (GHCl ₃ ) 3311, 1639, 1618 and 1567 cm ^-1 . MS: (m / e) 358 (M ⁺ ), 34-3, 340, 316, 299, 273 and 255 PMR; Q ^ ₁ (n, Benzylmethin), 4.23 (s, Carbinolmethin), 4.6 5.0 and 5.4 ^{from 3 to} 6.0 (s, vinyl) 6.81 (d, J = 2 Hz, arii), 6.82 ( dd, J = 8 and 2 Hz, ArH) and 7.05 (d, J = 8 Hz, ArH).

By means of this procedure is produced:

(241mg, 60%) of cis -3-Z2-benzyloxy-4- (1,1-dimethyiheptyl) phenyl 7-trans-4- (2-propenyl) cyclohexanol (500mg, 1.12mmol). Melting point: 124 to 125 ⁰ O (from pentane). IR: (CHCl ₃ ) 3571, 3333, 1642, -1618 and 1580. MS: (m / e) 358 (M ⁺ ), 340., 298, 286, 273 and 255.

PMR: Q ^ Jq ₁ 0.83 (n, terminal methyl), 1.23 (s, according to di methyl), 3 3 _j70 ζ _η ^ garbinolmethine), 4.6-5.1 and 5.2 6, 0 (n, vinyl H), 6.70 (d, J = 2 Hz, ArH). 6.82 (dd, J = 8 and 2 Hz, ArH), and 7.03 (d, J = 8 Hz, ArH).

-ιοί -

2 1 821 4

Analysis: Calculated for Found:

C, 80.39; H, 10.68 %. C, 80.52; H, 10.57 %,

To a solution of 3- / 4- (1,1-dimethylheptyl) -2-hydroxyphenyl-4- (2-propenyl-cyclohexanol (2.15 g, 6 _{ Ο3 mmol), (mixture of isomers) in dichloromethane (15 ml). pyridinium chlorochromate (2.59S, 12.1 mmol) was added, the reaction mixture was stirred at room temperature for 2 hours, diluted with ether, diatomaceous earth was added (?) and the mixture was filtered through magnesium sulfate (?, d. The evaporated solid was purified by column chromatography on 200 g silica gel eluted with 20 % ether-pentane to give 250 mg of the crude title compound, which was further purified by preparative thin-layer chromatography on two 20 cm χ 20 cm χ 2 mm silica gel plates Purified twice with 20 % ether-pentane to give 200 mg (9.3%) of the title compound as an oil.

IR: (CHCl ₃ ) 3571, 3390, 1718, 1650, 1626 and 1577 cm ^-1 . "" (M / e) 356 (M ⁺ ), 341, 338, 314, 288, 271, 257, 253 and 229.

0.79 (n, terminal methyl), 1.22 (s, according to dimethyl), 4.8 ^ 5.2 and 5.4-6.1 (n, vinyl H), 6,7- (η, ArH) and 6.82 (d, J = 8 Hz, ArIl).

Analysis: Calculated for C ₂₄ H ₃₅ O _2: C, 80.85; H, 10.18 %. Found: C, 80.92; H, 9.86%.

Example 35:

trans-3 ^ 2-B ^{e Z Z 0} SZz ^ z ( lxl ~ §i ^me i ί} <Ζ ™ ® fiiSi ^ EiiSSyiZz ^ r ^ "" (P £ 2 ~

A mixture of trans-3/2-benzyloxy-4- (1,1-dimethylheptyl)

-102- 2 1821

phenyl 7~4- (2-propenyl cyclohexanone (17.0 g, 38.1 mmol), ethylene glycol (47.2 g, 0.762 mol) and p-toluenesulfonic acid monohydrate (250 mg) in benzene (200 ml) was allowed to stand for 3 hours The reaction mixture was cooled and added to a mixture of 1N sodium hydroxide (200 ml), ether (100 ml) and pentane (100 ml). The organic extract was washed twice with 200 ml Wash portions of water, twice with 200 ml portions of water, twice with 200 ml portions of saturated sodium chloride, dry over magnesium sulfate, and evaporate to obtain a quantitative amount of the title compound: IR: (OHOiU) 1656, 1626, and 1587 cm "" ¹ .

MS: (m / e) 490 (M ⁺ ), 4-75, 450, 449, 448, 446, 407, 405, 399, 383 and 91. -

PMR: ODOL * ^{0) 82} ^ ³¹ ' ^{terminal methyls} ), 1.22 (s, according to DiODOL · ⁾ ,

methyl), '*' 3.1 (n, β-cylmethyne), 3.90 (s, ethylene ketal), 4.6-5.0 and 5.2-6.0 (n, vinyl H), 5.07 ( s, benzylmethylene), 6.81 (d, J = 2Hz, ArH), 6.81 (dd, J = 8 and 2Hz, ArH) and 7.07 (d, J = 8Hz, ArH).

Beispiel_36:

butenyl ^ cyclohexanone

A mixture of trans-3/2-benzyloxy-4- (1,1-dimethylheptyl) phenyl 7-4- (2-butenyl) cyclohexanone ethylenecarboxylate (700mg, 1.38mmol), dioxane (20ml) and 2 N hydrochloric acid (20 ml) was refluxed for 1 1/2 hours. The reaction mixture was cooled, poured into ice-water (500 ml) and extracted with ether (300 ml). The ethereal extract was extracted with two 200 ml (300 ml). The ether extract was washed with two 200 ml portions of saturated sodium bicarbonate, dried over magnesium sulfate and evaporated

218214

"" ¹

and gave a quantitative yield of the tite compound

in the form of an oil.

IE: (GHOl ₃ ) 1715, 1616, and 1575 cm "

MS: (π / β) -460 (M ⁺ ), 403, 375, 369, 363, 313, 273, 271 and

R _f : 0.43 (silica gel, 25% ether-pentane).

In the same way was produced:

gentenyl_) cyclohexanone

in a quantitative yield in the form of an oil of trans-3_ _/ 2-benzyloxy-4- ₍ 1,1-dimethylheptyl) phenyl) -4- ₍ 2-pentenyl)

cyclohexanone ethylene ketal (540 mg, ip4 mmol).

R _f : 0.57 (silica gel, 33 % ether-pentane).

Example 37 ^

By the procedures set forth in Examples 18, 19, 35-37, compounds of the following formula wherein ZV is as defined herein and Ro ^f 2 is prebpenyl, propyl, 2-butenyl, butyl and pentyl are prepared.

OH

Z-V /

-2-h ^ droxy; gheny _n ^JL7-cis-4-r l · meth5 -

- ιόν- 2 1821 4

cyclohexanol and ghe nyjL7 - ^ - me t hy 1 cy c 1 ohe xano η

A mixture of 3- / 2 "-benzyloxy-4- (1,1-dimethylheptyl) -phenyl-4-methylcyclohex-2-enone and 391 mg 5 % Pd-on-carbon / 50 % water in methanol (15 ml). The reaction mixture was filtered through diatomaceous earth with ethyl acetate and evaporated The residue was purified by column chromatography on silica gel (200 g) eluting with 50 % ether-hexane to give the product Sequence of elution 758 mg of a mixture of ketones and 820 mg (53 %) of the title cyclodexaline crystallized from cyclohexane The mixture of ketones was further purified by preparative thin-layer chromatography on five 20 χ 20 cm χ 2 mm silica gel plates eluting four times with dichloromethane to give 112 mg (7-2 %) of the title ketone in the form of an oil.

Melting point: 134 to 135 ⁰ O.

IR: (GHCl ₃ ) 3623, 3333, 1626 and 1585 cm ^-1 "(m / e) 332 (M ⁺ ), 314, 247 and 229.

PMR: ^ _{1 r} 0.69 (d, J = 7 Hz, C-4-methyl), 0.85 (n, terminal it methyl) 1.26 (s, according to dimethyl), 3.2 (η, Benzylmethin), 3.8 _(s; Oarbinolmethin), 5.05 (s, OH) and 6.7 to 7.1 (s, ArH).

Analysis: Calculated for C ₂₂ II ₃₆ O ₂ : G, 97.46; H, 10.92 %.

Found C, 79.40; H, 10.72%.

title ketone:

IR: (GHOl ₃ ) 3623, 3390, 1634 and 1582 cm ^-1 .

MS: (m / e) 330 (M ⁺ ), 315, 312, 288, 273, 271 and 245.

- 2 18214

PlViR: Q ¹ ^ ₁ 0.82 (η, terminal methyl), 0.88 (d, J = 7Hz, C-4-methyl) i 1.26 (s, according to dimethyl) and 6.83 (s , all ArH),

Beisgiel_39:

5- ^(2-r Benzylox5 -4- (1 _JL 1-dimethylhegt2l) ghen2l) -3 ~ Bisthox2 ~ ^ '~ methyl-2-cyclohexen-1-one

To a -78 ⁰ G end point solution of O ^ mol Lithiodiisopropylamid in 500 ml of tetrahydrofuran (from 50.5 g, 0.5 mol diisopropylamine and 417 ^ l of 1.2M η-butyllithium in hexane) is added dropwise (30 mm) a Solution of 217 g (0.5 mol) of 5- (2-benzyloxy-4- (1,1-dimethylheptyl) phenyl) -3-methoxy-2-cyclohexan-1-one in 250 ml of tetrahydrofuran. The reaction mixture is stirred for 30 minutes at -78 ⁰ G, followed by the addition of 179 g (1.0 mol) Hexamethylphosphoraraid and 78.1 g (0.55 mol) of methyl iodide follows. The reaction mixture is allowed to slowly reach room temperature, then it is stirred for 1 hour and quenched by the addition of 10 ml of water. The reaction mixture is evaporated under reduced pressure to remove tetrahydrofuran and added to 1 liter of ice water 1 liter of ether. The ether extract is washed with three 1 liter portions of water, dried over magnesium sulfate and evaporated to give the title compound in almost pure form. The title compound is purified by column chromatography on 2 kg of silica gel eluting with ether-pentane.

By repeating the procedure of this example, but using the appropriate Rp'I and the appropriate 5- / 2-berizyloxy-4- (Z- ¥ /) phenyl_7-3-alkoxy-2-cyclohexen-1-one of Example 4 are compounds with the following formula

2 18214

wherein R ⁰ , Z and W are as defined in Example 4 and R ₂ 'is methyl, n-propyl, n-hexyl, 3-butenyl.

1-dime-thylheptyl) -ghenyl _j 7- ^ _i 5-dime thy 1-cy_clohep_tanon

Having To a -78 solution of G ⁰ 17,4.g (0.10 mol) Bibromrnethan and 21.7 g (0.050 mol) of 3 ~ / 2 "-benzyloxy-4- (1,1-diiaethylheptyl) _{phenyl7_4)} 5_diiaethylcyclohexanon in 100 ml '.Tetrahydrofuran is added dropwise a solution of Lithiumdicyclohexylaciid (0.10 mol) in 100 ml of tetrahydrofuran over the course of 2 hours. the reaktionsgeniisch is stirred at -78 ⁰ C for 1 hour, then (by the addition of 2 ml The reaction mixture is added to 300 ml of ether and 200 ml of water The ether extract is dried over magnesium sulfate and evaporated The crude product is purified by column chromatography on 500 g of silica gel eluting with ether-pentane and yields pure 3 ~ / 2 ~ -benzyloxy-4- (1,1-dimethylheptyl) -pheny_l7_1-dibr offline of 1, 4, 5-dimethylcyclohexanol.

To a -78 ⁰ C solution of 30.4 g (0.050 mol)

- 107- 2 1 821 4

3- _i / 2-benzyloxy-4-) 1,1-dimethyl thyheptyl) -phenyl 1,71-dibromomethyl-4,5-dimethylcyclohexane oil in 150 ml of tetrahydrofuran are slowly added 47.7 ml (0.105 Mol) of n-butyllithium (2.2 M in hexane). The reaction solution is further for 2 hours at -78 ⁰ C and stirred for 10 minutes at O ⁰ G and then quenched by pouring into 300 ml ice-cold 1N hydrochloric acid. The quenched reaction mixture is extracted with two 250 ml portions of ether, the combined extract is washed with 250 ml of saturated sodium chloride, dried over magnesium sulfate and evaporated. The residue is purified by column chromatography on 500 g of silica gel while bleeding with ether-pentane to give the title compound.

Similarly, the other 3- / 2-benzyloxy-4- (Z-W) phenyl-7-cyclohexanones described herein are converted to the corresponding glycophenone derivatives.

By reducing it so using the procedures of; Examples 18 and 19 produced compounds are obtained the corresponding 3- / 2-hydroxy-'4- (Z-W) phenyl 7cycloheptanols.

The products of Example 40 are subjected to the ring extension procedure of this example to give the corresponding 3-Z 1 -Benzyloxy-4- (ZW) phenyl-7-cyclooctanones, which are then purified by the procedures of Examples 18 and 19 to give the corresponding cyclooctanols having the following formula. in which the variables correspond to the definition in the examples can be reduced.

&. I 0 £ I

Example 42:

General Formulation of the Hydrochloride Salt An excess of hydrogen chloride is passed into a solution of the appropriate compound of Formula IA-ID having a pyridyl group, and the resulting precipitate is separated and recovered from a suitable solvent, e.g., methanol, ether; 1:10) recrystallized.

Similarly, the hydrobromide, sulfate, nitrate, phosphate, acetate; Butyrate, gatrat, malonai, maleate, fumarate, malate, glycolate, gluconate, lactate, salicylate, sulfonyl salicylate, succinate, pamoate, tartrate and embonate salts,

Example 43s

xanol 2 * -O-heolisuccinate ester ernatriu ^^ αΞal · z To a solution containing O ⁰ O from 1.00 g (3 * 14 cis-3- / ² ^ - (1,1-dimethylheptyl) -2-hydroxyplienyI7cyclohex 0.323 g (3.14 mmol) of 4-N, H-dimethylaminopyridine are added anol in 3 ml of dichloromethane, to which 0.314 g of (3> 14 miviol) suc acid are added slowly, in 1 ml of dichloromethane, to the resulting solution, The reaction mixture is stirred for 4 hours at ⁰ ° C., then 3.14 ml of 1N hydrochloric acid are added slowly, the reaction mixture is stirred for a further 5 minutes and then added to 100 ml of water / 100 ml of dichloromethane evaporated.

18214

The residue is dissolved in 5 ml of ethanol and 3.14 ml of 1N sodium hydroxide in ethanol are added. The addition of ether leads to crystallization. Recrystallization from ethanol-ether gives the title compound. By replacing sodium hydroxide with potassium hydroxide in the above process, the potassium salt is recovered.

Using this procedure, the other compounds described herein are converted to their hemisuccinate esters. ·.

Example 44:

1-Dime t hy Ihepty ^ ^ -hydroxy pheny 17 - cyclohexanol 2 ^t -0-phosphate ester monosodium salt To a ^{0 0} G- containing slurry of o, 126 g (3.14 mmol) of potassium hydride in 3 ml of dimethylformamide is a solution of 1 Added 00 g (3.14 mmol) of cis-3- / 3- (1,1-dimethy1-heptyl) -2-hadroxyphenyI7cyclohexanol in 3 ml of dimethylformamide. After cessation of gas evolution (10 minutes), 0.932 g (3.14 mmol) of dibenzylphosphorochloridate is added slowly. The reaction mixture is stirred for 1 hour and then added to 200 ml of ether / 100 ml of water. The ether extract is washed with two 100 ml portions of water, dried over magnesium sulfate and evaporated to a residue. The residue is mixed with 1.0 g of 5% platinum on carbon and 25 ml of ethanol and stirred under a hydrogen atmosphere for 3 hours. The reaction mixture is filtered through diatomaceous earth and 3 ml of 1N sodium hydroxide in ethanol are slowly added to the filtrate.

-no.- 2 1 021 4

The addition of ether leads to the crystallization of the product. Recrystallization from ethanol then gives the title compound.

Similarly, the other compounds described herein are converted to their phosphate ester sodium salts and by exchanging sodium hydroxide for potassium hydroxide in their corresponding potassium salts.

Example 4-5;

10.0 mg of 3- / 4- (1,1-dimethylheptyl) -2-hydroxyphenyl 17 cyclohexanol are intimately mixed and ground with 900 mg of starch. The mixture is then filled into elastic gelatin capsules so that each capsule contains 10 mg of drug and 90 mg of starch.

Example 46;

A tablet foundation is made by mixing the below

cited ingredients produced?

Sucrose 80.3 parts

Tapioca starch 13.2 parts

Magnesium stearate 6.5 parts

Sufficient trans-3/2-hydroxy-4- (2- (5-phenylpentyloxy)) -phenyl7cyclohexanol is mixed into this base to give tablets containing 0.1, 0.5, 1, 5, 10

and 25 mg drug can be obtained.

Example 47;

Suspensions of 3 ~ / 2T ~ 1 (1,1-dimethylheptyl) -2-hydroxyphenyl cyclohexanone are prepared by adding sufficient amounts

- in - 2 1 021 4

of the drug to 0.5 % metylcellulose to give suspensions containing 0.05, 1, 0.5, 1.5 and 10 mg of drug per ml.

Presentation A

ff-Q -Bezyloxypheny ^^ - methylpropionitrile A solution of 295 (1.32 mol) of 2- (3-benzyloxyphenyl) acetonitrile in 200 ml of dimethyl sulfoxide and a solution of 420 ml of a solution of 1500 ml of methylsulfoxide saturated with methyl bromide During the above addition (30 minutes) and then for 1 1/2 hours, methyl bromide was bubbled constantly through the reaction mixture keeping the reaction temperature at 50 ° C by ice-cooling. The reaction mixture was added to 2 liters of water / 2 kg of ice and the resulting mixture extracted four times with 1 liter of ether. The combined ether extracts were washed twice with 1 liter of water, once with 1 liter of saturated sodium chloride, dried over magnesium sulfate and evaporated to give 325 g (98 % ) of the product in the form of an oil.

₀ " ¹ .

PMR; JJjQ ₁ - 1.70 (s, methyl), 5.12 (s, methylene), 6.8-7.5

(m, ArH) ^ and 7.45 (s, PhH) ₁ IR; (CHOI ₃ ) 2247, 1616 and 1603 cm "MS; m / e 251 (M ⁺ ), 236, 160 and 91.

Illustration B

2- (3-Benzyl-oxyphenyl ) -2-m- ethyl · pional-dehydroxide To a 15 C solution of 325 g (1.25 mol)

2 1021 4

2- (3-benzyloxyphenyl) -2-methylpropionitrile in 1.85 liter of tetrahydrofuran were added 1.6 mol of diisobutylaluminum hydride in the form of a 1 x, 3Μ solution in hexane (the reaction temperature was maintained at 15 "to 18 ⁰ G) .The reaction mixture was allowed to reach room temperature and it was (temperature = 30 ⁰ O) was further gerührt.Es for 2 hours followed by the addition of a Lysung of I70 ml of concentrated sulfuric acid in 670 ml water quenched. "the resulting mixture was allowed to reach room temperature, and stirring was continued for 2 hours. The organic layer was separated and the aqueous phase was extracted once with 1 liter of ether. The combined organic phase was washed with 500 ml of water and 500 ml of saturated sodium chloride, dried over magnesium sulfate and evaporated to give 315 g (99%) of the title product.

PMRi Q ¹ QQ ₁ 1,4-3 '(s, methyls), 5,08 (s methylenes), 6,8 -

7 _t 3 (m, ArIi), 7.4- (s, PhH) and 9.55 C s, aldehyde). IR; (ODOI ₃ ) 1742 and 1613 cm " ¹

MS: 254 (M ⁺ ), 259 and 9I.

Display 0

1- .Be Nzyloxy-3 (1, i-dim ethyl-2-hept- enyl) benzene To a 15 ⁰ C-containing solution of 1.8 moles of diisyl sodium (from sodium hydride and dimethyl sulfoxide) in 2 liters of dimethyl sulfoxide were portionwise 768 g (1.8 mol) Pentyltriphenyiphosphoniumbromid gegeben.Die resulting slurry was stirred for 15 minutes at 15 to 20 ⁰ C, then 315 g of 2- (3-benzyloxyphenyl) -2-methylpropionaldehyde is added slowly (1.24 mol) (reaction temperature = 30 ⁰ O).

2 1 821 4

The resulting mixture was stirred for 4 hours at room temperature and then added to 6 liters of ice-water. The quenched reaction mixture was extracted four times with 1-liter portions of 50 % ither-pentane. The combined extract was washed twice with 1 liter of water and once with 1 liter of saturated sodium chloride, then dried over magnesium sulfate to give an oil. evaporated. Crystallization of this oil from 50 % ether-pentane (to remove triphenylphosphine oxide), filtration and evaporation of the filtrate gave 559 S oil. The crude oil was purified by column chromatography on 2 kg of silica gel, eluting with 20 % hexane-dichloromethane, to give 217 g of C? 7 $> of the product as an oil.

PMRj ^ ₁ o, 75 (bt, J = 6Hz, terminal methyl), 1,1

(m, two ^ side chain methylenes), 1.43 (s, gem dimethyl), 1.60 (m, allylmethylene), 5 pounds 9 (s, benzylmethylene), 5.28 (dt, J = 12 and 6 Hz, vinyl H), 5.70 (dd, J = 12 and 1 Hz, vinyl H), 6.7-7 _t 3 (m, ArH) and 7.42 (s, PhII).

IR: (CHCl ₃ ) 1610 and 1587 cm ^-1 .

IVIS; m / e 308 (M ⁺ ), 293, 274, 265, 251, 239, 225, 217 and

Similarly, there were prepared: 1-Benzyl oxy-3- (1, i-dimethyloot g-enylbenzene ) (13.5 g, 70 %) from 15.75 g (0.062 mol) of 2- (3-benzyloxyphenyl) - 2-methyl-propionaldehyde and 37.5 S (0.0899 mol) of hexyltriphrylphosphonium bromide. The product was an oil.

PMRj TMS 0.78 (m, terminal side-chain methyl),

ODCI ₁ (s, according to J Dimethyl), 4.97 (s, benzylethermethylene),

5.23 (m, vinyl H), 3 57 _t (d, J = 11 Hz, vinyl H) and 6.6 7.4 (m, ArH and PhH).

2 1821

IR: (CHd ₃ ) 1608 and 1582 cm ^-1 .

MS: m / e 322 (M ⁺ ), 307, 279, 274, 265 and 231;

1-benzyl ο ^ -3 - ( "I _t 1, -dimethyl-2-propenyl) benzene as an oil · (.23,0 g, 91%) of 2- (3-benzyloxyphenyl) -2-me-bhylpropionaldehyd ( 25.5 g, 0.10 mol) and methyltriphenylphosphonium bromide (40.3 g, 0.113 mol).

PM: ^ ₁ 1.40 (s, gem.Dimethyl), 4.90 (dd, J = 18 and

2 Hz, vinyl ³ H), 4.90 (dd, J = 10 and 2 Hz, vinyl H) 5.05 (s, benzylethermethylene), 6.03 (dd, J - 18 and 10 Hz, vinyl

H) and 6.7-7.6 (m, ArH and PhH).

IR: (CHCl ₃ ) 1650, 1608 and 1587 cm ^-1 .

MS: m / e 252 (M ⁺ ), 237, 183, 161 and 91. "

1-Benzyloxy-3- (1- _t -1-dimethyl -2-bu-tenyl) -benzene as an oil (37.3 g, 77 %) of 2- (3-benzyloxyphenyl) -2-niethylpropionaldehyde (46.2 g , 0.202 mol).

PMR: ^ ₁ 1.22 (d, J = 6Hz, vinylmethyl), 1.41

(s, Dimetnyl, 5.03 (s, benzylethermethylene), 5.0 5.8 (m ₎ vinyl H), 6.6-7.5 (M, ixH and PhH). IR: (CHCl ₃ X 1661, 1626, 1621, 1608 and 1587 cm ^-1 . MS: m / e 266 (M ⁺ ), 251, 226, 183, 175 and 91.

1-Benzyl-3- (1,1-dimethyl-2-pentenyl) benzene as an oil (31 g, 74 %) of 2- (3-benzyloxyphenyl) -2-methylpropionaldehyde (40.0 g, 0.157 Mole) and propyltriphenylphosphonium bromide (66.7 g, 0.173 mol). ',

IR: (CHCl ₃ ) 1626 and 1600 cm ^-1 ,

(m / e) 280 (M ⁺ ), 265, 251, 237, 225, 211, 189, 147 and

2 18214

PMR: Q ^ q ₁ 0.62 (t, J = 7 Hz, methyl), 1.40 (s, acc.

Dimethyl), ^ 5.00 (s, benzylmethylene), 5.20 (dt, J = 11 and 7Hz, vinyl H), 5.59 (dt, J = 11 and 1 Hz, vinyl H) and 6.6. 7.4 (m, ArH).

1-Benzyloxy-3- (1J-dimethyl-2-hexenyl) benzene as an oil (35 g, 76 %) of 2- (3-benzyloxyphenyl) -2-methylpropionaldehyde (40.0 g, 0.157 mol) and butyltriphenylphosphonium bromide (69 , 0 1, 0.173 mol)

IR: (OHOIo) 1623 and 1600 cm "* ¹ .

IvIS: (m / e) 294 (M ⁺ ), 279, 265, 251, 255, and 9I.

PME: QpQ ₁ 0.69 (m, terminal methyl), 1.42 (s, acc.

Dimethyl, ^ 5.09 (s, benzylmethylene), 5.4 (m, .Vinyl H), 5 77 _t (d, J s 12 Hz, vinyl H) and 6.75 -7.7 (m, ArH) .

1 ~ benzyloxy-3 -. (1 _{1-dimethyl-2-nonenyl?)} Benzene · as an oil (34.5 g, 75%) of 2- (3-Benzylo2qyphenyl) -2-methylpropionaldehyde (40.0 g, 0.157 Mol) and heptyltriphenylphosphonium bromide (60.0 g, 0.138 mol)

R ~ :. 0.72 (silica gel), 33 % ether-cyclohexane) _o

1- Benzyl : xy -3- ( 1,1-diethyl-2-decenyl) benzene as an oil (43 g, 78%) of 2 ~ (3-benzyloxyphenyl) -2-methylpropionaldehyde (40.0 g , 0.157 mole) and octyltriphenylphosphonium bromide (81.0 g, 0.178 mole).

IR: (OHOI ₃ ) 1621 and 1600 cm ^-1 .

MS: (m / e) (M ⁺ ), 335 , 308, 281, 251 and 91.

PME: "3 ^ 0.83 (m, terminal methyl), 1.37 (s, acc.

Dimethyl ^ 5.03 (s, benzylmethylene), 5.23 (dt, J = 11

2.18214

and 7Hz, vinyl H), 5.54 (bd, J = 11Hz, vinyl H), and 6.65, 7.35 (m, ArH).

as oil (36 g,

63%) of 2- (3-benzyloxyphenyl) -2-methylpropionaldehyde (40.0 g, 0.157 mol) and nonylt-butylphosphonium bromide (81.1 s, 0.173 mol)

IR: (GHCI ₃ ) 1613 and 1592 cm ^-1

MS: (m / e) 364 (M ⁺ ), 349, 321, 295, 273, 251 and 9I.

0.87 (m, terminal methyl), 1.38 (s, acc.

Dimethyl), ³ 5.03 (s, benzylmethylene), 5.25 (dt, J = 6 Hz and, vinyl H), 5.65 (bd, J = 12 Hz, vinyl H) and 6.65 to 7, 6 (m, ArH).

Presentation D

3- (1,1 ~ dimethylheptyl) phenol

A mixture of 65 g (0.211 mol) of 2- (3-benzyloxyphenyl) -2-methyl-cis-oct-3-ene and 7.5 g of 10% palladium-on-carbon in 100 ml of ethanol was stirred for 1 hour in a Parr apparatus hydrogenated at a hydrogen pressure of 50 psi. After a reaction time of 1 hour and 2 hours, another 7.5 g portions of 10% palladium on carbon were added and the reaction was carried out for a further 12 hours. The reaction mixture was filtered through diatomaceous earth with ethanol and the filtrate was evaporated to an oil. The oil was purified by column chromatography on 1 kg of silica gel eluting with 50% hexane-dichloromethane to give 105 g (78%) of product as an oil.

2 18214

.Bar:. ^ ₁ . 0.85 (bt, terminal methyl), 1-1.9 (m, methylene, 1.29 (s, gem dimethyl), 4.98 (s, phenol H) and 6.6-7.4 ( m, ArH)

IR: (CHOI ₃ ) 3571.3311 and 1592 cm * " ¹ MS, m / e 220 (M ⁺ ), 205 and 135.

In the same way were prepared: 3- (1,1-Dirnethyloctyl) phenol in a yield of 82 % (7.8 g) from 13.0 g (0.0406 mol) of 1-benzyloxy-3- (1,1- dimethyl-oct-2-enyl) benzene.

It was obtained as oil with the following characteristics:

B / iS HvIR: CDGIo 0.85 (m, terminal methyl), 1.27 (s, acc.

Dimethyl), 5.25 (bs, OH) and 6.6-7.4 (m, ArH).

IR: (CHCl ₃ ) 3571, 3279, 1563 and 1527 cm ^-1 .

MS: m / e 234 (M ⁺ ), 2.19, 191, 178, 164, 149, 135 and 121.

3 "(1,1-dimethylpropyl) phenol as an oil (11.7%, 78%) of 1-benzyl o: xy-3- (1,1-dimethyl-2-propenyl) benzene (23.0 g , 0.0912 mol).

PER: 5SL 0.67 (t, J = 7Hz, terminal methyl), 1.23

KjXJKj I * -j

(s, according to dimethyl), 1.58 (q, J = Hz, methylene), 6.03 (s, OH)

and 6.6-7.4 (m, ArH).

IR: (CHCl ₃ ) 3534.3300, 1613 and 1587 cm ^-1 .

MS jm / e 164 (M ⁺ ), 149, 135 and 108;

3- (1,1- D- imethylbutyl) phenol as an oil (21.0 g, 84%) of 1-benzyloxy-3- (1,1-dimethyl-2-butenyl) benzene (37.3S, 0.140 mol).

PMR: Q ^ ₁ 0.85 (m, tenainales methyl), 1.18 (s, acc.

Dimethyl), ³ 5.42 (bs, OH) and 6.5-7.3 (m, ArH).

2 1021 4

IR: (CHGI ₃ ) 3623, 3448 and 1613 cm ^-1 .

MS: m / e 178 (M ⁺ ), 163, 135, 121 and 1o7.

3, (1,1-dimethylpentyl) phenol as an oil (16 g, 75%) of 1-benzylosy-3- (1,1-dimethyl-2-pentenyl) benzene (31.0 g, 0.111 mol).

IR: (CHGI ₃ ) 3636, 3390, 1634, 1623 and 1605 cm ^-1 MS: (m / e) I92 (M ⁺ ), 135 and 108.

rm / ra

^miR: CDC1 ° » ⁸² ^ ^m> ^ ⁶ * ^ ¹ )» ¹ » ²⁶ (s, gem.Dimethyl)

and 3 6.5-7.4 (m, ArH).

3- (1,1-Dimethylhephenol as an oil (18 g, 74%) of 1-benzyloxy-3- (1,1-dimethyl-2-hexenyl) benzene (35.0 g, 0.110 ').

IR: (OHGI ₃ ) 3650, 3390 and 1626 (wide) cm " ¹ _T

MS: (m / e) 206 (M ⁺ ), I9I, 177, 163, 149 and 135.

PMR: J ^ Q ₁ 0.80 (m, methyl), 1.22 (s, gem dimethyl) and ³ 6.5-7.3 (m, ArH).

3- (1 _t 1-Dimethylnonyl ) phenol as an oil (20.6 g, 86%) of 1-benzyloxy-3- (1,1-dimethyl-2-nonenyl) benzene (34.5 g, 0.103 mol ). IR: (CHOI ₃ ) 3636, 3378 and 1613 (wide) cm "" ¹ . IaS: (m / e) 248 (H ⁺ ), 233, 192, 178 and 135.

PMR: JpQ ₁ 0.86 (m, terminal methyl), 1.22 (s, according to dimethyl), ³ 5.37 (S, OH) and 6.5-7.3 (M, ArH).

3- (1,1- Dimethyldecyl) phenol as an oil (21.0 g, 65%) of 1-benzyloxy-3- (1,1-dimethyl-2-decenyl) benzene (43.0 g, 0.123

IR: (CHCI ₃₎ 3636.3333 and I6I3 (broad) cm ^'1.

MS: (m / e) 262 (M ⁺ ), 247, 206, I9I, I.78, 166, I55, and 135.

-ns.- 2 18214

PMR: JSiS ₁ 0.88 (m, terminal methyl), 1.23 (s, according to

methyl) and ³ 6.5-7.4 (m, ArH).

^{as an oil} ( ²¹ 81-77 %) of 1-benzyloxy-3- (1-1-c-dimethyl-2-undoeoenyl) benzene (36 g, 0.099 mol), IR: (GHOl ₃ ) 3534-, 3279 and 1597 cm ^-1 MS: (m / e) 276 (M ⁺ ), 261, 220, 184 and 135. TW · "!

PME: Q ^ Jq ₁ 0.87 (m, terminal methyl), 1.22 (s, according to dimethyl), 3 ^ ₁ (broad, OH) and 6.5-7.3 (m, ArH).

Presentation E

To a solution comprising O ⁰ G of 110 g (0.50 mol) of 2-C3-hydroxyphenyl) -2-methyl octane in 200 ml of carbon tetrachloride was added dropwise a solution of 80 g (.O ₁ ¹ PO mol) of bromine in 90 ml of carbon tetrachloride (reaction temperature = 30 ⁰ G with cooling). The reaction mixture was further stirred for 15 minutes and then evaporated to give 150 g (100%) of product as an oil.

PMR: J ^ q ₁ 0.85 (bt, terminal methyl), 0.8-1.9 (m, methylenes), ^ 1.28 (s, according to dimethyl), 5.4 (bs, phenolic H) , 6.78 (dd, J = 8 and 2 Hz, 0-6-ArH) ₁ 7.02 (d, J = 2 Hz, C-2-ArH) and 7.37 (d, J = 8 Hz, G - ^ - Ar). IR: (GHGl ₃ ) 3559, 3289 and 1585 cm ^-1 . MS: m / e 300, 289 (M ⁺ ), 215, 213, 201, 199, 187 and 195.

In the same way were prepared: Qz ^ ^z H ^ om ~ 3-hy_dro ^: xyP ¹¹⁶ SSi) ~ 2-methyl-nonanoan in a yield of 82 % (8.5 g) as an oil from 7.8 g (0.033 mol ) of 2- (3-hydroxyphenyl) -2-methylnonane _B

PMR: ° or the like ^'86 ^ ^terminal methyl), 1.27 Cs, gem. Di- 'methyl), ³ 5.50 (bs, OH), 6.83 (dd, J = 8 and 2 Hz, ArH),

2 1 © 21 4

7.08 (d, J = 2 Hz, ArH) and 7.43 (d, J = 8 Hz, ArH)

IK: (CHCl ₃ ) 3279, 1613 and 1587 cm ^-1 .

IvIS: m / e 314, 312 (M ⁺ ), 212, 210, 185 and 187.

as an oil (12.7 S, 98%) of 2- (3-hydroxyphenyl) -2-methylbutane) - 49.50 g, 0.0579 MoI). HvIR: ^ ₁ 0.67 (t, J = 7 Hz, terminal methyl), 1.23

(s, according to dimethyl), 1.56 (q, J = 7 Hz, methylene), 5.2 (bs, OH), 6.84 (dd, J = 8 Hz, ArH).

IR: (CHCL ₃ ) 3521, 3279, 1608, 1600 and 1577 cm ^-1 .

MS: m / e 244, 242 (M ⁺ ), 229, 227, 215 ,. 213, 187 and 185.

2- (4-bromo-3-h 2; droxyphengl) -2-meth 2; 1-pentane as oil (29.9 g> 99%), of 2- (3-hydroxyphenyl-2-methylpentane (21.0 g, 0.118 MoI).

BAR: ^ ₁ 0.83 (m, terminal methyl), 1.22 (s, according to dimethyl), ^ 5.42 (bs, OH), 6.75 (dd, J = 8 and 2 Hz, ArH) , 6.98 (d, J = 2 Hz, ArH) and 7.32 (d, J = 8 Hz, ArH). IR: (CHCl ₃ ) 3610, 3333, 1618 and 1600 cm ^-1 .

WiS: m / e 258, 256 (M ⁺ ), 243, 241, 215, 213, 201, 199, 187 and 185.

as oil (22.8 g,

100 %) of -2- (3-hydroxypyryl) -2-methylhexane (16.0 g, 0.0833 mol).

IR: (CHCl ₃ ) 3610, 3333, and 1600 cm ^-1 . MS: m / e 272 and 270 (M ⁺ ), 215, 213, 287

(Quantitative) of 2- (3-hydroxyphenyl) -2-methylheptane (20.0 g, 0.971 mol). '. '

IR: (CHCl ₃ ) 3584, 3333 and 1600 cm ^-1 . MS: m / e 286 and 284 (M ⁺ ), 215, 213, 187 and 185.

- 121 - 2 1 821 4

EMR: Q ¹ ^ q ₁ 0.87 (m, terminal methyl), 1.30 (s, according to dimethyl). ³ 5.49 (bs, OH), 6.83 (dd, J = 8 and 2 Hz, ArH), 7.07 (d, J = 2 Hz, ArII) and 7.42 (d, J = 8 Hz , ArH).

^{as an} oil (23.2 g,

85 fo) of 2- (3-hydroxyphenyl-2-methyldecane (20.6 g, '0.0831 MoI),

IR: (CHCl ₃ ), 3571, 3333 and 1661 cm ^-1 . MS: m / e 328 and 326 (M ⁺ ) 313, 311, 215 and 213.

HIiR: QβGi ° » ⁸² Cm, terminal methyl), 1.30 (s, according to dimethyl), 3 5, ^ 9 (s, OH), 6.82 (dd, J = 8 and 2 Hz, ArH), 7.07 (d, J * = 2 Hz, ArH) and 7.41 (d, J = 8 Hz, ArH).

2- (4-Bromo-3-hydroxyphenyl 2-2-methylundecane as an oil (quantitative) of 2- (3-hydroxyphenyl) -2-methylene decane (21.0 g, 0.0802 mol)

IR: (CHCl ₃ ) 3571, 3333 and 1600 (wide) cm ^-1 . MS: m / e 342 and 340 (M ⁺ ), 215, 213, 187 and 185.

HviR: Qßci ° ^'86 ^ ^{m' terminal} methyls), 1.22 (s, gem DiQßci methyl), ³ 5.45 (bs, OH), 6.74 (dd, J = 8 and 2 Hz, ArH). , 6.99 (d, J = 2 Hz, ArH) and 7.33 (d, J = 8 Hz, ArII).

^{as an} oil (22.0 g,

81 %) of 2- (3-hydroxyphenyl) -2-methyldodecane (21.0 g, 0.0761 mol) ₄

IR: (CHCl ₃₎ 3597, 3333, 1613 and 1592 cm "^'1. MS: m / e 356 and 254 (M ⁺ ), 340, 338, 215 and 213.

FMR: ¹ QQ i ^ 0.92 (m, terminal methyl), 1.29, ^3, 5.47 (bs, OH), 6.81 (dd, J = 8 and 2 Hz, (s, gem dimethyl). Ar H). 7.06 (d, J = 2 Hz, ArH) and 7.41 (d, J = 8 Hz, ArII).

- ¹²² - 2 1821 4.

Presentation P

To a -18 ⁰ O-containing slurry of 23.0 g (0.575 mol) of potassium hydroxide in 400 ml of Ν, Ν-dimethylformamide over a period of 45 minutes, a solution of 150 g (0.5 mol) of 2- (4-bromo -3 ~ hydroxypheriyl) -2-methyloctane in 400 ml of N, N-Dimethy! formamide added (reaction temperature = -15 ⁰ G). The reaction mixture was stirred for a further 15 minutes, after which a solution of 98.3 g (0.575 mol) of benzylbromide in 200 ml of Ν, Ν-dimethylformamide was added. The mixture was then warmed to room temperature and stirred again for 30 minutes. It was quenched by the addition of 6 liters of ice water. The quenched mixture was extracted six times with 500 ml of ether. The combined extract was washed twice with 1 liter portions of water and once with 1 liter of saturated sodium chloride, dried over magnesium sulfate and evaporated to a quantitative yield of the title product.

Tf T-5

PMR: QQQ ₁ 0.85 (bt, terminal methyl), 0.8-2.0 (m, methylenes), J 1.22 (s, according to dimethyl), 5.17 (s, benzylmethylene) and 6, 7 - 7.6 (two multiplets, ArH and PhH), IR: (OHGIo) 1592 and 1575 cm ^-1 .

MS: m / e 390, 388 (M ⁺ ), 375, 373, 354, 352, 305, 303 and

was in a

Yield of 95 % (10.4 g) from 2- (3-hydroxy-4-bromophenyl) -2-methylnonane (8.5 g, 0.027 mol), sodium hydride (0.744 g, 0.031 mol) and benzyl bromide (5, 3 g, 0.031 mol) in the form of an oil.

.PMR: J ^ q ₁ 0.87 (terminal methyl), 1.23 (s, according to dimethyl), 3 5 ^ ₈ ( _S) benzylethermethylene), 6.8 (dd, J = 8 and 2 Hz, ArH ), 6.97 (d, J = 2 Hz, ArH) and 7.43 (in, ArIi) and PhH).

- 123 - 2 1 821 4

IRi (GHGIo) 1600 and 1575 a "" ¹

MS: m / e 404, 402 (M ⁺ ), 305, 303,

, 5 g, 88%)

of 2- (4-bromo-3-hydroxyphenyl) -2-diethylpropane (38.0 g, 0.166 mol) Melting point: 52 to 54 ⁰ G (from pentane). PMR: Q 1 (J ₁ 1.25 (s, t-butyl), 5.18 (s, benzyl ether hiethylene),

6.7-7.0 ^ (m, two ArH) and 7.2-7.6 (m, an ArH and PhH).

IR: (GHGl ₃₎ 1600 and 1585 cm ^"1 ₀

MS: m / e 320, 318 (M ⁺ ), 305, 303, 239 and 223.

^ ^as ^ ¹ ( ² → 9S »99 %) of 2- (4-bromo-3-hydroxyphenyl) -2-ethylbutane (17.3 S, 0.0777 KoI),

IR: (GHGl ₃ ) 1600 and 1585 cm ^-1 ,

IvLS: m / e 334, 332 (M ⁺ ), 319, 317, 309, 303, 253, 223 and 9I .. -

2 ^ 3 ^ -4 ^ Benz2lox bromophenyl) -2-metnylpentan as an oil (34.3 S $ 99%) of 2- (4-ßi-Ohi-3-liy <iroxyphenyl) -2-raeth3 ^T lpentan ( 25.7 g, 0.100 mol).

PIviR: Q ^ Jq ₁ 0.80 (ra, terminal Iv.ethyl), 1.23 (s, according to DiQ ^ Jq ₁ ,,,,,

methyl), * 5.12 (s, Benzyläthermethylen), 6.6 to 6.9 (m, two arii) and 7.1 to 7.5 (m, ArH and PhII). IRi (GHGl ₃ ) 1610 and 1595 cdi " ¹

MS: m / e 3 ^ 8, 346 (M ⁺ ), 333, 331, 305, 303 and 91.

2'-3'-benzyloxy-4-bromo-2-yl] -2-meth 2-hexane as an oil (30 g, 98 %) of 2 ~ (4-bromo-3-hydroxyphenyl) -2-methylhexane) 22 , 7S, IR: (GHGl ₃ ) 1605 and 1592 cm ^-1 ,

fm / e 363 and 361 (M ⁺ ), 305 and 303.

PMR: 'qwi O »? ⁸ ( ^m > terminal methyl), 1.18 (s, "gem, di

- 2 1821 4

methyl), 5.12 (s, benzylmethylene), 6.65-6.9 (m, ArH) and 7.15-7.6 (m, ArH and Ph).

2 - (3-Benzyloxy) -4-bromophen (1) -2-methylheptane as an oil (auanti

tively). of 2 ~ (4-bromo-3-hydroxypienyl) -2-methylheptane (23.0 g, 0.0806 mol)

IRs (CHcI ₃ ) 1600 and 1582 cm ^-1 .

MS: m / e 376 and 374 (M ⁺ ), 305, 303, 215 and 213 »PMR: cjxji °» ⁸⁰ ( ^m > ^ perminal methyl), 1,19 (s, according to dimethyl), 3 5,12 (s, benzylmethylene), 6.65-6.95 (m, ArH), 7.15-7.6 (M, ArH and Ph).

as an oil (quantitative) of 2- (4-bromo-3-hydroxyphenyl) -2-methyldecane (^ 3.2 g, 0.0712 mol).

IR: (OHCl ₃ ) 1600 and 1585 cm ^-1

MS: m / e 418 and 416 (M ⁺ ), 305-, 303, 215 and 213.

PMR: ODOL ° '9 ^ ^{1 m> terminal} methyl), 1.26 (s, gem dimethyl), 3 ^ 5 9 _(Sj benzylmethylene), · 6.7 to 7.0 (m, ArH) and 7. 25-7.65 (m, ArH and Ph).

⁰ S »82 %) of 2- (4-bromo-3-hydroxyphenyl) -2-methyl-hexane (27.3 g, 0.113 mol).

IR: (CHCl ₃ ) 1605 and 1587 cm ^-1 .

MSt m / e 432 and 430 (M ⁺ ), 305, 303, 215 and 213.

PMR: ^ ₁ 0.90 (m, terminal methyl), 1.24 (s, according to dimethyl), 5, 8 (s, benzylmethane), 6.7-7.0 (m, ArIi) and 7, 2-7.6 (m, ArH and Ph).

2 ~ (3-benzene2loc2, -4-bromo-phenyl) -2-methyldodecane as an oil (27.5 g, 100 %) of 2- (4-bromo-3-hydroxyphenyl) -2-methyldodecane (22.0 g,

218214

0.0620 mol).

IE: (CHCl ₃ ), 1605 and 1592 cm ^-1 .

MS: m / e 446 and 444 (M ⁺ ), 305 and 303. TMS

PlVlE: methyl),

"3

0.86 (m, terminal methyl), 1.21 (s, according to di-5,13 (s, benzylmethylene), 6,7-6,95 (m, ArH) and 7,2-7 _t ^ ( m, ArH and Ph).

The compounds listed below are prepared from appropriate reactants according to the procedures given for Preparations G-F:

Z-W

° 6 ^Η 5 4-pyridyl O (CH ₃ ) ₂ (CH ₂ ) ₃ 2-pyridyl / "ί / Ήττ Ν Γ nil Λ ν / \ VyIlο / pV wXIq J / tf ~ s OH (GH ₃ ) (CH ₂ ) ₂ , ^C 6 ^H 5 (CH ₂ ) ₅ H (OH ₂ ) ₁ * He. (CHP) .. H ° 6 ^Η 5

.ι ". 218214

Presentation Z

2- (3-J3enzyloxy-4-bromopheDyl) -2-ynethylootane (100 g, 0.257 mol) in tetrahydrofuran (500 mL) was added slowly to magnesium 70-80 (12.3 g, 0.51A mol ) at such a rate as to maintain reflux. Upon completion of the addition, the reaction mixture was stirred until it had reached room temperature. E _{3 vmr} ^ _e then further cooled to ^{0 0 0} . In the course of 25 minutes dimethylformamide (29.8 ml, 0.385 mol) was added dropwise to the reaction mixture (reaction temperature 10 ⁰ C). The reaction mixture was allowed to warm, then stirred for 40 minutes at room temperature. The reaction mixture was quenched by the addition to a saturated aqueous solution of cold ammonium chloride (1800 ml) and the product was extracted with ether (1 liter). The ether extract was dried over magnesium sulfate and evaporated to a quantitative yield of the title compound as an oil.

IR: (OHGl ₃ ) 1693, 1618 and 1580 cm ^-1

IvIS: m / e 338 (M ⁺ ), 309, 253, 247 and 91. PMR: Q ^ oi ° " ⁸² (" teminal methyl), 1.30 (s, according to dimethyl), 5.18 ^ (s , Benzylmethylene), 7.0 (m, two ArH), 7.39 (bs, Ph), 7.76 (d, J = 8Hz, ArH) and 10.53 (s, GHO).

Using this procedure, the 2-benzyloxy-4- (Z-W) bromobenzenes of the representations F, H, I, N and W are converted to the corresponding benzyldehydes of the formula:

O O

Z-W

where Z and W correspond to the definition in these representations

Claims (1)

%% 0 fm Erfindcingsanspruch A process for the preparation of a compound of the formula: ca Z-W v / orin Q is a phenyl protecting group,
Z Alkyleη having 1 to 13 carbon atoms or. - (alk ^) -O- (alkp) -, wherein alk, and alkp alkylene having 1 to 13 carbon atoms, with the proviso that the sum of the carbon atoms in Calk ,,) plus (alkp) not greater than 13 and η and m is 0 or 1, and V is hydrogen, pyridyl or the group-hydrogen, fluorine or chlorine, characterized in that a compound of the formula withw ^ = OHC wherein Q is a phenyl-protecting group, and Z and W are as defined above, a Wittig reaction with 1-triphenylphosphoranylidene-2-propanone in an inert solvent. 218214 subjected to a temperature lying between room temperature and reflux temperature, the product thus obtained is treated with a dialkyl malonate of the formula: COOR ₅ CH. wherein R _{1 is} - alkyl having 1 to 4 carbon atoms, is reacted in an inert solvent at a temperature of 25 ⁰ C to reflux temperature and the resulting product is decarboxylated by reaction with aqueous sodium or potassium hydroxide at a temperature between 50 and 100 ⁰ C lying temperature *