DD140454A5 - PROCESS FOR PREPARING 3-STROKE BRANCHES ON 2-HYDROXY-4- (SUBSTITUTED) -PHENYL SQUARE BRACKETS TO CYCLOAL CANNON - Google Patents

Abstract

The invention relates to a process for the preparation of certain 3- [2-hydroxy- ~ 4 ~ (substituted) phenyl] cycloalkanone ^ and cycloalkanols and of their derivatives. These compounds are useful as CNS agents, especially as analgesics, tranquilizers, sedatives and antiaxiols, or as anticonvulsants, diaretics and antidiarrheals. For example, to prepare 3 ™ [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] cyclohexanone, 2- (3-benzyloxy-4-bromo-phenyl) -2-methylmethanoctane in tetrahydrofuran is reacted with a magnesium metal. After boiling at reflux, copper (I) iodine is added, followed by reaction with a solution of 2-cyclohexan-1-one in tetrahydrofuran and later with hydrochloric acid.

Description

AV Ahren to Hers tellung von.anal g etic 3- / 2 ~ llydroxy -A - (sxxbsti-substituted) phenyl / cycloalkanon- and cycloalkanol agents ^

.the invention ^

The invention relates to certain C. cycloalkanones _f cycloalkanols and unsaturated analogues thereof having from 5 to 8 carbon atoms in the cycloalkyl ring and an S-hydroxy-substituted (ZW-substituted) phenylgruene in the 3-position, wherein Z is alkylene 1 to 13 carbon atoms or (alk) -O «(alkp) _s in which m and η-each are O or 1 and (alk) and (alkp) are each alkylene of 1 to 13 carbon atoms under the presciption that the Sum of carbon atoms in (all.) Plus

Bulldozing

) is not more than 13; and ¥ = hydrogen, phenyl, chlorophenyl, fluorophenyl or pyridyl; Derivatives thereof, and a process for their preparation. The products are useful as CNS agents, especially as analgesics, "tx'aaquillizers, sedatives and antianxial agents in mammals, including humans, or as anticonvulsants, diuretics and antidarrhoika in mammals, including humans."

Characteristic of the known technical solutions:

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

U.S. Patent 3,576,887, issued April 27, 1971, discloses a series of 1- (1'-hydroxy) alkyl-2-o-hydroxyphenylcyclohexane or -ene compounds useful as intermediates in the preparation of 6,6-Dialkyltetraiiydro- and -hexahydrodibenzo [b, dj-pyrans serve as passivating agents for. the central nervous system are useful.

It has now been found that certain cycloalkanones, cycloalkanols and unsaturated analogues thereof having a 2-hydroxy-4- (substituted) phenyl group at the 3-position (formula I below) are effective as CUS agents, especially as Analgesics, tranquilizers, sedatives and antianxiolytics 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

OR,

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

A. , B

I - A (Aj B ₅ taken individually)

II - A (A, B taken together)

and

I - G (A _s B taken individually) I ~ D

II - G (A, B taken together) II ~ D

wherein the dashed lines represent an optical double bond at one of the locations where R-. in this case can not be * wesend;

when ea alone is taken, represents hydrogen;

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

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- is selected from the group comprising hydrogen, alkanoyl having 1 to 5 carbon atoms, benzyl, -P (O) (OH) p and the mono- and disodium and potassium salts thereof,

-CO- (CH ₂ ) -

the sodium and potassium salts thereof, and wherein: p is an integer of 1 to 4; R ^ and R, when taken individually, are each selected from the group consisting of hydrogen and alkyl of 1 to 4 carbon atoms; Rf and Rr when combined with the nitrogen to which they are attached form a 5- or 6-membered one

4 -

form heterocyclic ring selected from the group consisting of piperidino, pyrrolo, pyrrolidino, morpholino and N-alkylpiperazino having 1 "to 4 carbon atoms in the alkyl group

_{2 is selected} from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 3 to 6 carbon atoms, phenyl and phenylalkyl of 1 to 4 carbon atoms in the aikyl moiety;

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

R is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, provided that'R. Is hydrogen, if R ^ is methyl}

Z is (a) alkylene of 1 to 13 carbon atoms; (b) - (alk ..) -O- (alkp) _n * - comprising group wherein each (alk ^) and (alkp) alkylene having 1 to 13 carbon atoms is provided that the sum of the carbon atoms in (alk.,) plus (alkp) is not greater than 13; m and η je = 0 or 1; and

V / from the hydrogen, pyridyl (where W is selected from the group consisting of hydrogen, chlorine and chlorine, comprehensive group is selected »

The dashed lines in the compounds of formula I, de h. Phrasing IA r ID »represents the optical presence of a.

Double bond at one of these sites.

~ 5

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 is a basic ester component. In compounds in which two basic groups are present, of course, are polyoic acid adducting salts. Possible representatives of such pharmaceutically acceptable acid addition salts are mineral acid salts such as hydrochloride , Hydrobroraid, sulfate j phosphate} l \ titrate _s salts of organic acids such as citrate, acetate, sulfosalicylate, tartrate, glycolate, malate, malonate malay, · pamoate, salicylate, stearate, phthalate, succinate, gluconate, 2 ~ hydroxy-3 naphthoate, lactate, mandelate and methanesulfonate ©

Compounds of formula IA-ID wherein A and B, when taken together, are oxo and R is hydrogen, are in solution in equilibrium with their hemicetal forms. The keto and hemicetal forms of the compounds of formula I are included in the invention _e

Compounds of formula IA-ID wherein A is hydrogen and B are hydroxy contain asymmetric centers at the 1-, 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 (-ZV /) of the phenyl ring. The cis relationship between the substituent 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 component is preferred since it has the stronger (quantitative) biological activity. For the same reason will

also the trans-3,4-inclusion in compounds of formula IA-ID, wherein A and B, when taken together, represent oxo.

For the sake of simplicity, the above formulas show the racemic bonds. However, the above formulas are considered to be typical of the racemic modifications of the compounds of this invention, the diastolic mixtures, the pure enantiomers and the plastomers thereof, and also include the utility of the racemic mixture, the diastereomeric mixture, and the pure enantiomers and diastereomers determined using the biological evaluation procedures described below.

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

(ice and

trans)

(in which no stereochemistry is present).

where Z, VJ, R _? and R_ correspond to the above definition; Y is selected from the group consisting of cyano and formyl; t is an integer lying between 1 and 8;

. BJ is selected from the V / on Hydrogen and alkyl of 1 "to 4 carbon atoms group comprising; and ^·%

Q is selected from the group consisting of -CH ₂ -, -CH ₂ -CH (R ₄ ) -, CII ₂ -CH ₂ -CH (R ₄ ) - and (R ₁ -) -

The compounds of the formula IV are representatives of the hemiketal and ketal forms of the saturated cycloalkyl compounds of the formula I (AD) ₅ in which A and B together represent oxo «

Compounds of the formulas IA-ID, wherein A and B together are 0x0, are preferred because of their greater biological activity than those of other compounds described herein. J A and B, when taken individually, are hydrogen or hydroxy, R _{2 is} hydrogen or Is alkyl, R _{1 is} Y / oxygen or alkanoyl, R ₁ is hydrogen or methyl; R, Y / oxygen or alkyl are and Z and W have the meanings given below;

Alkylene having 8 to 11 carbon atoms

Alkylene of 4 to 7 carbon atoms

_a -0- (alk ₂ -) _a

₁ ) _m -0- (alk ₂ )

m η

, Pyridyl, pyridyl

Preferred compounds of the formula I, and especially the saturated cycloalkyl compounds of the formula Ϊ, are the favorable compounds in which: R «and R -3 represent hydrogen

Z ~ -C (CH ₃ ) g (CHg) ₆ and W = hydrogen; Z = C "alkyl ^ n and W = phenyl;

Z = -O-alkylene having 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; Rg = hydrogen, methyl, propyl or propenyl; R ₃ = hydrogen; and

 R * = hydrogen or methyl.

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

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

The saturated Cycloalkylvejrbindungen invention having the formula I, wherein R- is hydrogen, are prepared from the corresponding 2-bromo-5- (ZW-substituted) phenol by means of a series of reactions that include the first step, the protection of the phenol group , Suitable protecting groups are those which do not interfere with the subsequent reactions and which can be removed under conditions which do not cause undesirable reactions at other sites of the compounds or products produced therefrom. Representatives of such Schutsgruppen are methyl j ethyl, benzyl or substituted benzyl, in which the substituent for example alkyl with 1

to 4 carbon atoms, halogen (Cl, Br _s P, J) and alkoxy having 1 to 4 carbon atoms * The Ätherschutz- or -blockierungsgruppen can acid in acetic acid or 48% wäßriger.Bromwasserstoff be removed acid by the application of hydrogen bromide, the reaction is carried out at elevated temperatures and preferably at the reflux temperature * However, when Z = - (alk.) -0 ~ (alk _o) - ₅ must be used to Verbinderung the cleavage of ether linkage other acids such as trifluoroacetic acid or PoIyphosphorsäure. Other reagents such as hydriodic acid, pyridine hydrochloride or hydrobromide can be used to remove ether protecting groups such as methyl or ethyl groups. "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. On the other hand, they can be removed by solvolysis using trifluoroacetic acid. A further procedure consists of treating with η-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 done easily and quickly by a person skilled in the art. The suitability and effectiveness of a group as a 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.

The protected 2-bromo-5- (Z-W s3substituted) phenol becomes thereafter

-ί- 207 79

with magnesium in an inert solvent, generally in the presence of a promoter, e.g. For example, copper (I) salts viie ~ chloride, bromide and iodide (to promote 1,4-addition) with the appropriate 4-R ₂ -2-cycloalken-1-one (e.g., B ₆ 4- Ro ~ 2'-cyclohexen-1-one). Suitable Reactants inert • Solvents are cyclic and acyclic ethers such as tetrahydrofuran, dioxane and dimethyl ether of ethylene glycol (diglyme). Las Grignard reagent is prepared in a known manner, for example, by boiling a mixture of 1 molar proportion of bromine reactant and 2 molar proportions of magnesium in an inert solvent, e.g. The resulting mixture is then cooled to about 0 to -20 ⁰ G, then copper (I) iodide is added and then the corresponding 2-cycloalkene-1-one at between about 0 and -20 ⁰ C lying temperature. The amount of copper (I) -godide used is not critical and can be very different. Mole ratios between about 0.2 and about 0.02 mole / mole of bromine reactant give satisfactory yields of the cycloalkanone in which the phenolic hydroxy group is protected (formulas IA-ID, R 1 = a protecting group; R 1 = H; A-1 B = oxo ).

The protected cycloalkanone is then treated with an appropriate deprotecting reagent. The benzyl group is best removed by the method described above. If the protective group is an alkyl group (methyl or ethyl), it is prepared by the methods described above or by treatment with e.g. Be pyridine hydrochloride removed.

When Rp is an alkenyl group, the cycloalkenones produced in this manner serve as intermediates for the preparation of the corresponding cycloalkenones (IA-ID) ₅ wherein R _{2 is} alkyl.

The cycloalkanol compounds of formula I are prepared from the protected cycloalkanones by reduction. In this step, sodium borohydride 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 with hydroxyl solvents (methanol _s ethanol , Water) _t that their use as a solvent is possible. "Temperatures generally between about -40 ⁰ C and 30 ⁰ C are applied. Lower temperatures, even to about -70 ⁰ C, can be used to increase the selectivity of re ~ production used "Higher temperatures produces a reaction of the Hatriumborhydrids with the hydroxylic« ¥ / hen higher temperatures, "seem appropriate or required for a specific reduction "Isopropyl alcohol or the dimethyl ether of diethylene glycol used as a solvent." Potassium tri-sec-butylborohydride is sometimes preferred as the reducing agent because it promotes the stereoselective formation of the trans-1,3-phenylcycloalcohol in dry tetrahydrofuran at -50 ⁰ C under a lying ?! temperature, to which equimolar amounts of the ketone compound and reducing agent can be used. "

Reducing agents such as lithium borohydride _s Diisobutylaluminiuni "hydride or lithium aluminum hydride, which may also be used, require anhydrous conditions and solvents that are not hydroxyls, such as 1,2-dimethoxyethane, tetrahydrofuran, diethyl ether, dimethyl ether of Athylenglycol.

The cycloalkanols of formula I, wherein A is hydrogen and B and OR are each hydroxy, can of course be obtained directly by catalytic reduction of the protected cycloalkanones via balladium on charcoal or by catalytic reduction or chemical reduction of the unprotected cycloalkanone (Formula

I, A + B = όζ o, 0R.J = OH) can be obtained using the reducing agents described above.

In practice, preference is given to the unprotected cycloalkanols of the formula I (A = H, B + OR ₁ = OH) via the reduction of the benzyl-protected cycloalkones (formula I, A + B = oxo, OR ₁ = benzyloxy) as described above because it allows the stereochemical control of reduction and formation of the cis-hydroxyepimer as the major product, thus facilitating the separation and purification of epimer alcohols.

Compounds of Formulas IA-ID wherein the double bond is at the 2,3-position are synthesized by the Grignard reaction of the appropriately protected 2-bromo-5- (ZW-substituted) -phenol with a 3-alkoxy ™ 2 -cycloalkene-1-one (having one to four carbon atoms in the alkoxy group) in an inert solvent at a temperature between about -30 and +10 ⁰ G. The protected cycloalkenone compound thus produced is then deprotected as described above and reduced to the corresponding cycloalkenol. On the other hand, the protected cycloalkenone is chemically, z. By using Hatriumcryrhydr® Ld, to which protected cycloalkenol is then deprotected for the regeneration of the phenolic hydroxy group.

Compounds of Formulas IA-ID wherein the double bond is at the _3S 4 position are prepared from compounds of Formulas IA-ID wherein A + B is oxo and the double bond is at the 2,3-position. The process comprises the ketalization of the corresponding 2,3-unsaturated compounds of the formulas IA-ID with an alkylene glycol having two to four carbon atoms in the presence of a dehydrating agent such as p-toluenesulfonic acid in a solvent such as benzene, where

by the azeotropic removal of the lifting product water is possible. · Isomerization of the double bond to the 3 ^ -unsaturated keto derivative takes place. Decalcification as a result of treatment with mild acid produces the 3 _s 4 "-unsaturated compounds of the formulas IA-ID, wherein A + B represents oxo * Reduction of the oxo group as described above gives the corresponding alcohol",

The protected cycloalk-2-enones (Formulas IA-ID, A + B = oxo _s R .. protective group) also serve as intermediates for compounds of the formula I ₉ wherein R 1 is methyl. The introduction of the R_ substituent is carried out by conjugate addition of Dimethylkupferlithiums to the corresponding Cycloalk-2-enone »The method consists of the reaction of the corresponding protected cycloalkenone with Dimethylkupferlithium in an inert solvent such as cyclic or acyclic ethers and especially in tetrahydrofuran at temperatures of 0 ^{0 0} C to -20 C. the organic reaction me tall means causes 1,4-addition to the protected cycloalkenone to form a tertiary carbon "the R ~ -substituted protected cycloalkanone is then deprotected and reduced or reduced and then after the exempted from the protection described above. It is also formed the 1,2-addition product.

Compounds of formula IB wherein the cycloalkyl moiety is saturated and wherein R 1 is other than hydrogen are prepared by reacting the corresponding 2-bromo-5- (ZW-substituted) phenol in which the phenol group is suitably as described above protected with magnesium to form the Grignard reagent as previously described. The geväonnene Grignard reagent is then treated, without isolation, at a reduced temperature, about +10 ⁰ C and -20 ⁰ C, with ujh-Dimethylforrnamid. The reaction mixture is allowed

then warmed to room temperature, and the product, a protected 2-hydroxy-4- (ZY / -substituted) benzaldehyde, is recovered by known methods. The benzaldehyde derivative is then converted via the Wittig reaction with the corresponding i-triphenylphosphoranylidene-2-alkanone in a reaction-solvent at a temperature ranging from about room temperature to the reflux temperature of the solvent in a te - (2-hydroxy-4- (ZW-substituted ) phenyl) -3-alkene-on. By the above-mentioned 2-propanone derivative, the formation of the cyclohexyl component is possible. The arylalkene-on produced in this way is then reacted with a dialkylmalonate, preferably an _s in which the alkyl groups have 1 to 4 carbon atoms, to cyclize the alkene-on. The reaction is carried out in an inert solvent such as an alcohol having 1 to 4 carbon atoms at a temperature of about 25 ⁰ C to the reflux temperature of the solvent.

The carbalkoxy-substituted cycloalkane dione compound produced is then decarboxylated by treatment with aqueous sodium or Kaiiumhydroxid at elevated temperature, ie, between about 50 ⁰ C and 100 ⁰ C, and the cycloalkanedione derivative is isolated by conventional known methods. It is then ketalized by reaction with methanol or another alcohol of up to 4 carbon atoms or an alkylene glycol of 2 to 4 carbon atoms in the presence of a dehydrating acid such as p-toluenesulfonic acid.

In the case of the cyclohexyl derivative, the 3-methoxy-2-cyclohexene-i-one derivative is then reacted with lithium aluminum hydride in an inert solvent such as diethyl ether, dioxane, tetrahydrofuran or diglyme at a temperature of about -10 ⁰ C to 10 ⁰ G and with worked up with dilute mineral acid. The resulting aryl-substituted-2

cyclohexen-1-one are then at a between about 0 ⁰ C and about -20 ⁰ C temperature lying treated with the corresponding Dialkylkupferlithium in. a suitable inert solvent such as hexane, diethyl ether or mixtures of these solvents, or in cyclic ethers, such as tetrahydrofuran The protected 3 - [4- (ZW) -substituted-2-hydroxyphenyl "3-5-R" -cycloalkanone is then deprotected and reduced or reduced according to the procedures described above, and then deprotected "

On the other hand, by reacting 5-E2-benzyloxy-4-bis (Z-W) phenyl-3-alkoxy-2-cyclohexene-1-ones with the appropriate Grignard reagent R.MgBr and subsequent acid hydrolysis, the corresponding 5-L forms. 2 ~ benzyloxy ~ 4 ~ (ZW) phenyl} -3-R / _- 2-cyclohexene-1. ~ One, which are then subsequently reduced catalytically to the corresponding cyclohexanones. Debenzylation as described above gives the 5-f2-hydroxy-4- (Z-W) -pheny1J-3-R / cyclohexanones, which are then reduced to the corresponding cyclohexanols as described above.

Compounds of formula IC wherein the cycloalkyl moiety is saturated and where R is other than hydrogen are prepared by ring extension of the cyclohexyl derivative. Reaction of the corresponding 5-12% benzyloxy-4- (ZW) -phenyl3-3-R / cyclohexanone with lithium dibromomethane in an inert solvent such as diethyl ether gives 1-dibromomethyl-S-Ls-benzyloxy (ZW). phenyl! -3-R, cyclohexanol. The further reaction of the 1-Dibrommethylcyclohexanols in an unreactive solvent such as -tetrahydrofuran with η-butyllithium gives 3- £ 2-hydroxy-4- (ZW) phenyl] ~ 5-cycloheptanones R. _s, the procedures from the above-described protection device is then in accordance with the freed and reduced or reduced and freed from protection ·

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

If R 1 is hydrogen in structure IA-IC, then it is possible, according to the procedures described above, to expand the rings of these structures to the methylene-larger ring, ie. to achieve IB-ID ₅ ·

The 2-bromo-5- (ZW- * substituted) phenol reactants are prepared by bromination of the corresponding 3 ~ (Z ~ W-substituted) phenol by standard methods such as by treatment with bromine in carbon tetrachloride at between 20 and 30 ^° C The necessary 3- (ZW-substituted) phenols, if they are unknown compounds, are obtained according to methods explained here. A convenient method for the preparation of reactants in which the Z-component is alkylene or (alk-) ~ 0- (alkp) - consists in the Wittig reaction of a corresponding aldehyde such as 2- (3-hydroxyphenyl) -2 -methylpropionaldehyde whose hydroxy group is protected by benzyl ether linkage. This aldehyde is then treated with the corresponding alkyltriphenylphosphoniumunbromide whose alkyl group extends the propionaldehyde group to the desired length. In a typical process, the aldehyde reactant becomes a slurry of sodium dimsyl and alkyltriphenylphosphonium bromide in dimethylsulfoxide at a temperature below 30 ° C, for example between 10 and 10 30 ⁰ G, given. When the reaction is complete, the alkene-substituted protected phenol is recovered by known methods. Hydrogenation of the alkene over palladium on charcoal then gives the intended 3- (2-W-substituted) phenol benzyl ether output (3-hydro

xyphenyl) substituted aldehyde and alkyltriphenylphosphonium bromide reactants, the intended 3- (Z-W-substituted) ~ phenol reactants are recovered

The representation of the corresponding 4-R _p -2 -cycloalkene-1-one allows the synthesis of the structures of formulas IA-B, wherein R _{A is} hydrogen, according to the procedures described above, The reaction of the corresponding 1 ^ -cycloalkanedione with an alcohol containing 1 to 4 carbon atoms and an acid catalyst of toluene sulfonic acid in an inert solvent, benzene or toluene, and in a water separation apparatus at temperatures at which the reaction solvent refluxes gives 3-alkoxy-2-cycloalkene-1 one "By reacting the corresponding 3-alkoxy-2-cycloalken-1-one with lithium diisopropylamide in an inert solvent viie Tetraliydrofuran in the presence of hexamethylphosphoramide and the corresponding R _? X, wherein X is bromide or iodide or any other suitable group, is obtained 4-R ₂ "3-alkoxy-2-cycloalkene" - = 1-one, which is 4-R ₂ -3-alkoxy-2-cycloalkene 1-one then with vjird Lithiumaluminiumhyürid in an inert solvent such as diethyl ether, at between -10 and 10 etvja ⁰ G temperatures lying reacted and filled with dilute mineral acid; The resulting 4-R2 ~ 2-cycloalkene-1-one is then converted using the procedure already described *

Compounds of formula IB-ID wherein the cycloalkyl moiety is saturated and wherein Rp and R * _ are each other other than hydrogen are prepared by reacting the appropriate 5 - [, 2-bensyloxy-4 ~ (ZW) phenyl} -3-metho : xy-2 cyclohex "en-1 -one with lithium diisopropylamide in an inert solvent at ei ~ ner low temperature," as -50 to -78 ⁰ C then be prepared hexamethylphosphoramide and the corresponding R ₂ ~ iodide (^ Forin R _{2 is} not hydrogen) is added to

a 5- ^ 2-benzyloxy-4- (ZW) phenyl} -3-methoxy-6-R ₂ -2-cyclohe: to generate en-1-one: x. Further reaction of the compound with the appropriate Grignard reagent R ¹ MgX (where R is alkyl) under the usual Grignard reaction conditions gives 3 ~ £ (2-benzyloxy-4- (ZW) phenyl) -4-R ₂ - 5-R ₄ ^l -5-cyclohexen-1-one Debenzylation and reduction of the compound by the procedures described above gives the intended 3-p-2-hydroxy-4- (ZW) phe ⁿ y3-3-4 Rp. Reduction of the double bond of the 3- {2-benzyloxy-4- (ZW) phenyl] -4-R-5-R ^ -oxyclohexen-1-one over Pd / C leads to the formation of .alpha.-cyclohexanol These latter derivatives serve as intermediates for the preparation of the corresponding cycloheptanone and cyclooctanone derivatives by the ring expansion process described above.

A convenient procedure that allows the selective alkylation of 3 - (2,4-dihydroxyphenyl) -cycloalkanones at the 4-hydroxy group, as a first step, the conversion of 3- (2,4-dihydroxyphenyl) 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 consists of reacting the 3- (2,4-dihydroxyphenyl) cycloalkanone with an orthoformic acid ester in solution in an alcohol corresponding to the alcohol component of the orthoformic acid ester. Trimethyl_, orthoformate and methanol are preferred reactants in conjunction with concentrated sulfuric acid, anhydrous hydrogen chloride or ammonium chloride as a catalyst.

The ketal thus produced is then prepared by reaction with a para alkylating agent such as WZX ₅ wherein W and Z are as defined above and Z is selected from chloro, bromo, mesyloxy (CH ₃ -SO ₂ -O) and tosyloxy (P-CH ₃ -C ₆ H ₄ -SO ₂ -O ") group in the presence of an acid acceptor, Z ₉ B, sodium or potassium carbonate, alkylated The alkylated ketal is then treated according to known methods by treatment with deketalized aqueous acid «

Another method for the preparation of 3- (ZW substituted) phenols wherein Z is alkyl or (alk-) -O- (alk, p) - includes the Wittig reaction with an appropriate phenol aldehyde or ketone , z _e B * 3-hydroxybenzaldehyde, or a 3- (hydroxyphenyl) alkyl ketone, in which the phenol hydroxy group is protected by conversion into the benzyl, methyl or ethyl ether. "By choosing the appropriate reactants, compounds having straight or branched alkylene groups (Z) are produced. "If a ketone, e.g. For example, when 3-hydroxyacetophenone _{9 is used} as the reactant, compounds are obtained in which Z has a methyl group on the carbon atom adjacent to the phenyl group.

The substitution of a methyl or Ä'thylgruppe in other places, eg. As the beta-carbon of the alkylene group is carried out by the choice of the appropriate Carboalkoxyalkylidentriphenylphosphoräns, z. B. (C ₆ Hc) ₃ P = C (R ¹ ) -COOC ₂ H ₅ . 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 (ζζΒmethyl), the alcohol is produced by catalytic reduction of the unsaturated ester using palladium-carbon, whereupon treatment of the thus-formed saturated ester with lithium aluminum hydride is carried out resulting alcohol to the

* · Ο

207 7? 9

corresponding toeylate or hesylate followed by alkylation of the tosylate or mesylate with an alkali metal salt of the appropriate HO- (alk ₂ ) -W reactant and finally removal of the protecting group yields the intended 3- (Z-W-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 H 0 ~ (alk ₂ ) -W in the presence of a suitable base (Wiliamson ether synthesis).

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-. The method consists of treating the bromo derivative with triphenyl phosphine to produce the corresponding triphenyl phosphonium bromide. Reaction of the triphenylphosphonium bromide with the appropriate aldehyde or ketone 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 more particularly 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 one tertiary alcohol in the presence of an acid _s z. For example, methanesulfonic acid. The general method consists of reacting a mixture of methanesulfonic acid and equimolar proportions of guaiacol and tertiary

tiärem alcohol at between about 30 ⁰ C and about 80 ⁰ C lying temperatures completed by .the reaction is substantially β The product is isolated by that the reaction mixture poured onto 3 £ is and is then extracted with an appropriate 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 of converting the hydroxy group to a dialkylphosphate group by reaction with a dialkylchlorophosphonate, e.g. By treating the dialkyl phosphate with lithium / ammonia and subsequent demethylation of the resulting alkylated methyl ether with boron tribromide or pyridine hydrochloride or other known demethylating agents, the proposed 3-alkylphenol is formed.

A convenient method for preparing compounds of the invention in which -ZV / = -O- (alk) -W is the use of 4-Brömresorcinol as starting material. The procedure requires protection of the two hydroxy groups of resorcinol by benzylation according to standard methods. In this method, the benzyl group is preferred as the protecting group, since it can be easily removed by catalytic hydrogenation without cleavage of the ether group -O-Calkp Other protecting groups such as alkyl (eg methyl or ethyl) may also be used. However, the benzyl protecting group is preferred, as it leads to fewer ITebenreaktionen. 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-dihydros: yphenyl) cycloalkanone which is in equilibrium with its hemiketal. The hemiketal is then converted into the corresponding C ₁ , -alkyl, 'ζ. Β. methyls

Ketal, converted by reaction, for example, with a Trialkylorthoformiat as / lrimethylorthof ormiat in a suitable solvent such as CJ, -alcohol, z «B. methanol, in the presence of concentrated sulfuric acid. The Alkylketal to this V / ice produced is then alkylated with the appropriate alkyl or Aralkylmethansulfonat or tosylate in the presence of -wasserfreiem Hairiumoder potassium carbonate VDE in a suitable unreactive solvent Η, ΙΤ-dimethylformamide at a between 75 OHD 100 ⁰ C temperature lying. This method has the advantage that simpler compounds can be used for the entire sequence of reactions. The O-alkylated or aralkylated ketal is then purified by reaction with, for example, hydrochloric acid to produce the corresponding 3- (2-hydroxy-4- [0- (alk ₂ ) _n '] phenyl) cycloalkanone, which is in equilibrium with its hemiketal, deketalized ·

Ba Compounds of the formulas IA-ID in which A and B taken together are oxo and R is hydrogen, in solution in equilibrium with the hemicetal form and some, in the crystalline state, are substantially completely present in the hemiketal form, are compounds of the Formulas IA-ID, wherein 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 3 taken together are methylene are readily prepared from the corresponding oxo compounds via the reaction with methylenetriphenylphosphorane or other appropriate methylid. The common method is to produce the Wittig reagent. h, of the methylidene, in situ, and immediately after the generation of methylidene in its reaction with the appropriate oxo compound. A convenient method for the production of the methylidene is the reaction of IT sodium hydride with dimethylsulfoxide

(TTatriumdimsyl) at a temperature lying between about 50 and 80 ⁰ C, usually until the evolution of hydrogen has ceased, followed by the reaction of the resulting Methylsulfinylcarbanion (Dimsyl) solution with, for example, methyltriphenylphosphonium bromide at between about 10 ⁰ C and about 80 ⁰ G lying temperature follows. The solution generated in this way of the ylide is then added to the appropriate oxo compound and the mixture is stirred at room temperature lying between ⁰ and 80 C temperatures. The methylene compound prepared in this way is isolated by known methods. Hydroboration-oxidation of the methylene compound then gives the hydroxymethyl derivative as explained herein. For the hydrobromination step, borane in tetrahydrofuran is preferred since it is commercially available and gives satisfactory yields of the intended hydroxymethyl compound. The reaction is generally carried out in tetrahydrofuran or diethylene glycol dimethyl ether (diglyme). The borane product is not isolated but oxidized directly to the hydroxymethyl compound with alkaline hydrogen peroxide, "

Other methods for producing the methylidene are known per se and can be used instead of the procedure described above. Typical procedures are described by Maercker in Organic Reactions, 14, 270 (1965) * In AEEN oxo compounds of the formulas IA-ID, the phenolic hydroxy group in V / are unsightly protected, for example by conversion to a Alkanoyloxyderivat "Of course, other protecting groups may be used. The hydroxyl group can be converted to ethers, such as tetrahydropyranyl ethers. However, the protection of the phenolic hydroxy group is not necessarily required if sufficient base is present to convert the phenolic hydroxy group to an alkoxide.

Esters of the compounds of the formulas IA-ID, wherein R-. Alkanoyl or -GO- (GH ₂ ) UR Rg can be readily prepared by reacting compounds of the formulas IA-ID wherein R 1 is hydrogen with the appropriate alkanoic acid or acid of the formula HOOG-

) WR R ^ in the presence of a condensing agent such as dicyclohexylcarbodiimide. On the other hand, they are prepared by reacting a compound of formula IA-ID with the appropriate alkanoic acid chloride or anhydride, e.g. 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 hydroxymethyl and OR ,, is hydroxy are prepared by acylation according to the procedures described above. Compounds in which only the R group (R-OH, CHOH) 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 way can be further acylated with another acylating agent to form a dicovered compound with different ester groups. "

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

Tests using pain-inducing heat stimulants

a) Analytical mouse test with hot plate

The method used is a modification of the method of Woolf e and Mac Donald, J. Pharmacol. Gxp. They "-,, 80, 300 - 307 (1944) * A regulated heat stimulus is applied to the feet of mice on a 1/8-inch thick aluminum plate. A '250 watt infrared heater with reflector is placed under the aluminum plate with thermistor

ren on the disc surface associated heat controller programs the heat lamp so that a constant temperature of 57 ⁰ G is maintained · Each mouse is in a folder from the hot plate glass cylinder (6 1 / ^ - inch diameter) is set, and begins the timing " When the Feet of the Mouse Touches the Plate * The mouse is observed for 1/2 hour and 2 hours after treatment with the test compound for the first ⁿ movements of one or both hind feet, or passed for 10 seconds without such movement are. Morphine has an MPE ₅₀ of 4-5.6 mg / kg (subcutaneously).

(b) analgesic use -Z ₁ UC kte st

Tail swallowing in mice was determined according to D'Amour and Smith, J. Pharmacol. Exp. · Ther., _72 * 74-79 (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 so that the beam of light can pass through the slot and focus on the tail. »Simultaneously a timer is switched on« The latency of a sudden twitch of the tail is determined. Untreated mice usually react within 3 to 4 seconds after irradiation with the lamp. The end point for protection is 10 seconds AEEN, Each mouse is 1/2 hour and 2 hours after treatment with morphine at Lind the Te compound tested morphine has an MPE ^ ₀ 3.2 to 5.6 mg / kg (subcutaneously) ,

c) Sch Wanz int e ^ e n ajichverfahr

The method is a modification of the method described by Benbasset et al. a. developed vascular procedure, Arch, int ...

»HS 434 (1959). Male albino mice (19 to

21 g) of strain Charles River CD-1 are weighed and marked for identification. For each drug treatment group, five animals are normally used, with each animal acting as its own control. For general investigative purposes, new test agents are administered initially at a dose of 56 mg / kg intraperitoneally or subcutaneously in a volume of 10 ml / kg Drug and 1/2 hour and 2 hours after administration, each animal is placed in a cylinder. Each cylinder is provided with holes which allow for adequate ventilation and is closed by means of a round-mouthed silicone stopper, through which the tail of the animal protrudes. The cylinder is held vertically and the tail is completely submerged in the constant temperature water bath (56 ^° C.). The end point of any attempt is an energetic jerky movement or twitching 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 damage, the trial is terminated after 10 seconds and the tail is removed from the water bath. The reaction latency is noted down to 0.5 seconds in seconds. A vehicle control and a standard of known potency are tested simultaneously with the candidate candidates. If the effectiveness of a test agent has not returned to baseline values after the 2-hour test point, reaction latencies are determined after 4 and 6 hours. A final measurement is taken after 24 hours if efficacy is still evident at the end of the test day.

Test using chemical shaman stimulants. Suppression of dysphoria

gracious twitching

Groups of 5 Carworth Farms CF-I mice each are administered subcutaneously or orally with saline, morphine, codeine or the test compound.

pretreated * Twenty minutes (for subcutaneous treatment) or fifty minutes (for oral treatment) later, each group is treated by intraperitoneal injection of phenylbenzoquinone, i. H. an irritant known to induce abdominal contractions. The mice are observed for 5 minutes after the onset or absence of twitches, starting 5 minutes after the stimulant is injected. The MPEj-Q values of the drug pretreatment to block the twitches are determined.

Aim of the Haffner Tail Method A Modification of the Haffner Method, Experimental Test of Pain Relieving Agents, Deutsch. Med. Wschr., 55, 731, 732 (1929) The effect of the test compound is used in aggressive attack reactions induced by a caudal stimulus * Male albino rats (50 to 60 g) of the CD strain Charles River (Sprague Dawley) are used »before the drug treatment and again for 1/2, 1, 2 and 3 hours after A 2.5 "Johns Hopkin ^& Bulldog" clamp is clamped onto the root of the rat's tail. "The endpoint of each trial is a clear attack and biting behavior against the perturbing stimulus, recording the latency of the attack in seconds »The clamp is removed after 30 seconds, -no attack was made, and the latency of the reaction is recorded as 30 seconds. 8 mg / kg (intraperitoneally).

Tests using electrical pain-promoting stimulants

The "back-spray " test

A modification of the back-fall-spring method of Tenen, Ps J _- Chopharmac ρ log ia, JM2, 278-285 B96S) is used for the determination of the pain threshold of male albino rats (175 to

200 g) of the CD strain Charles River (Sprague Dawley) are used. Before administration of the drug, the feet of each rat are immersed in a 20 % glycerol / brine solution. The animals are then placed in a chamber and allowed to withstand 1-second shocks at 30-second intervals 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 3.04mA , The behavior of each animal is assessed for (a) twitching, (b) squeaking, and (c) jumping or rapid advancing at the onset of shock. Single enhanced 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 a percentage of maximum potential effect ($ S £ PE). The $ LBP values of each group are statistically compared to the% MPE value of the standard and control values before taking the drug. The E-values are calculated as follows:

_ Test duration - control period_ * qq exposure duration - control period

The compounds of the invention, when used as analgesics by oral or p.a. 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 in the form of tablets, pills, powders or granules containing excipients such as starch, milk sugar, certain types of clay and so on , administered. They can be administered as capsules mixed with the same or similar excipients

Form oral suspensions, solutions, emulsions, syrups and elixirs which may contain flavoring or coloring agents. For. the oral administration of the therapeutic agents of the present invention are tablets or capsules containing from about OjOI to about 10 rag, suitable for most applications.

The physician will determine the amount most appropriate for a particular patient, and this will vary according to the age, weight, and response of the individual patient and the route of administration. However, in general, the initial amount of adult adulterate 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 per day »A favorable oral dose is between about 1 _s 0 and about 300 rag / day, the preferred dose is about 1.0 to 50 mg / day. A favorable parenteral dose is between about 0.1 to about 100 mg / day, the preferred between about 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 of the invention are prepared by mixing a weight portion of the medicament with nine weight percent of the weight of the drug.

share excipient like starch or milk sugar and. Filling the mixture into expandable gelatin capsules, each capsule containing 100 parts of the mixture. Tablets containing these compounds are prepared by blending suitable mixtures of medicament and standard ingredients used in the preparation of tablets, such as starch, excipients and lubricants, each tablet being 0.10 to 100 mg of drug per tablet · contains

Suspensions and solutions of these drugs, particularly those wherein R- (formulas I and II) is hydroxy, are often prepared just prior to use to problems in terms of durability of suspensions or solutions (such as _e precipitation) of the drug at to exclude storage "Compositions suitable for this purpose are generally available as dry solid compositions which are dissolved for administration by injection"

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

FROM

OH

Z-W Table I: A = H, B = OHj Table II: A + B =. oxo.

In the tables, the following abbreviations are used: PBQ = phenylbenzoquinone-induced writhing; TF = 'tail twitching; HP = hot plate; RTC = pinching of the rat's tail; and FJ = twitching - jumping «

The individual values in the tables are ED-Q values. A number followed by a number in brackets indicates the % protection observed at a given dose. Thus, 31 (56) means 31 % protection at a dose of 56 mg / kg body weight ·

Table I: Analgesic efficacy (rag / kg) of% protection (mg / kg), subcutaneous

PBQ

HP

PJ RTC

cis-OH trans-OH

cis-OH

trails-OH

cis-OH

trans-OH

cis-OH

cis-OH

trans-OH

trans-OH

trans-OH

cis-OH

cis-OH

H H

H H H H H H

C (CH ₃ ) ₂ (CH ₂ ) ₆ H 1,1 C (CH ₃ ) ₂ (CH ₂ ) ₆ H 3,8 trans -CH ₃ C (CHJ ₂ (CH ₂ ) _g H £ 56

H H 6.8

4.0 4.7

H H H H H H

trans-CH ₃ H

H H

H H

trans -CH ₃ H OCH (CH ₃ ) (CH ₂ ) ₃ C ₆ H ₅ 28 (56) OCH (CH ₃ ) (CH ₂ ) ₃ C ₆ H ₅ 38 C (CH ₃ ) ₂ (CH ₂ ) ₆ HC (CH _{3) 2} (CH _{2) 6} H

C (CH _{3) 2} (CH _{2) 6} H

C (CH _{3) 2} (CH _{2) 6} H

0 (0H ₂ ) ₄ C ₆ H ₅ > 56

O (CH ₂ ) ₄ C ₆ H ₅ <56

C (CH ₃ ) ₂ (CH ₂ ) ₆ H <1

1.53 IAgIO 65 (10) 5, 4 5 , 6 1.5 27 (10) 32 (1 0) 3, 5 7 , 7 57 (56) 36 (56) 0.5

Table II; Analgesic efficacy

(mg / kg) of% shu.tz (mg / kg), subcutaneously

A + B = O3CO

PBQ

HP

FJ

1 O H H C (CH ₃ ) ₂ (CH ₂ ) ₆ H 4.5 33 (10) 15.3 1 (a) 1 O O H H CH ₃ H C (CH ₃ ) ₂ (CH ₂ ) ₆ C (CH ₃ ) ₂ (CH ₂ ) ₆ H H 31 (56) 20 (56) 1 O H H OCH (CHO) (CH ₉ ), ^C 6 ^H 5 $ 56 1 O H (B) C (CH ₃ ) ₂ (CK ₂ ) ₆ H 20 (56) 2 O H H C (CH ₃ ) ₂ (CH ₂ ) ₆ H 2.15 58 (10) O O H H C (CH ₃ ) ₂ (CH ₂ ) ₆ H 15 (56) 1 1 O (c: O H H H H O O H'H 32 (56) 43 (56) 1 O cis-Ci I ₃ H C (CH ₃ ) ₂ (CH ₂ ) ₆ H 1.51 (a) = (b) = Benzyl ether P Zr analog. the phenolic OH group

(0). = Methylketalderivat IA - ineffective

Their effectiveness as diuretic agents is determined by the method of Von Lipschitz u. a. J. Pharmacol., 221x97 (1943), in which rats are used as experimental animals. The dose for this purpose is in the same range as that just mentioned with regard to the use of the compounds described herein as analgesic agents.

The antidiarrheal efficacy is demonstrated by a modification of the method of Heimegeers et al. · Modern Pharmacology Toxicology, Willem van Bever and Harbans LaI, Eds., T ₅ 68-73 (1976). · 18 hours before the trial, Charles River CD-1 rats (170-200 g) are placed in groups Housed cages. The animals must fast overnight overnight prior to administration of castor oil, but with water at their disposal * 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 EI -620 (a polyoxyethylated vegetable oil emulsifier, available from Antara Chemicals, I'iew York, KY) and 90 % brine, followed after one hour by the administration of castor oil (1 ml, orally). The animals are housed in small individual cages (20.5 x 1 χ 21 cm) with hanging grid floors. A disposable cardboard sheet is placed under the grid bottoms and examined for the presence or absence of diarrhea one hour after the castor oil has been dispensed. A vehicle / castor oil treatment group serves as a control for a daily test. The results are recorded as the number of animals that were protected one hour after administration. In general, the dosage levels associated with the use of these compounds as antidiarrhoeal are consistent with those used as analgesics.

The sedative effect of the compounds of the invention is demonstrated by their oral administration to rats in between

wa 0.01 and about 50 mg / kg of body weight were determined and observing the following reduction in spontaneous motor activity. The daily dose for 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 14-23 g in a vehicle used for antidiarrhoeal preparation. The mice are divided into groups of 5 animals each. On the day before the experiment, the mice get no putter on ITacht, but water at will. The treatments are carried out in quantities of 10 ml per kg with the aid of a 25-gauge injection needle. The test animals are treated with the test compound and one hour later an electroconvulsive shock of 5o mA is transcorneally applied at 60 Hz. At the same time, control experiments are carried out The electroconvulsive shock treatment elicits tonic extensor 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 the Blektrokonvulsionsschocks ·

Efficacy as an antianxiolant is determined in a similar manner as in the determination of anticonvulsant activity, with the difference that the convulsion inducing agent pentylenetetrazole was used in an amount of 120 mg / kg when administered intraperitoneally. This treatment causes clonic convulsions in less than 1 minute in over 95 % of treated control mice. Protection 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 houses 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 mouse's inability to stay on the wheel is taken as evidence of the effectiveness of the sedative depressant.

Aasführungsbei S

Example I ₁ :

A solution of 75.0 g (0.193 mol) .- 2- (3-benzyloxy-4-bromophenyl) -2-methyloctane in 200 ml of tetrahydrofuran was added slowly to 9 »25 g (0.386 mol) of magnesium metal with a sieve fineness of 70 to 80 mesh given. The resulting mixture was boiled for 20 minutes at reflux, then cooled to -18 ⁰ C. Bs vmrde copper (I) iodine (1.84 g> 9 _S 7 mol) was added and stirring continued for 10 minutes. To the resulting mixture vmrde slowly added a solution of 18.5 g (0.193 mol) 2-0yclohexen-1-one in 40 ml of tetrahydrofuran at such a rate that the reaction temperature was maintained below -3 ⁰ C by salt-ice-cooling , The reaction mixture was stirred for a further 30 minutes (t <0 ^° C.) and then added to 500 ml of 211 hydrochloric acid and 2 liters of ice-water. The quenched reaction mixture was extracted three times with 500 ml portions of ether. The combined extracts were washed twice with 100 ml portions of water, twice with 100 ml portions of saturated sodium chloride, dried over magnesium sulfate and evaporated to an oil. The oil was purified by column chromatography to 1.6 kg of silica gel eluting with 20% ether-cyclohexane to give 62.5 g _(79} 7%) of product in the form of oil,

cf ™ ^S 0.84 (m, terminal methyl), 1.27 (s, according to dime-CDCl ₃

ethyl), 3.32 (bm, benzylmethine), 5.06 (s, benzylmethylene), 6.7

7.3 (m, ArH ₁ ) and 7.32 (s, PhH).

IR: (CHCl ₃ ) 1709, 1613 and 1575. cm ^-1

MS: m / e 406 (M ⁺ ), 362, 321, 315 and 91.

The above compounds are selected from the appropriate 2-benzyloxy-4-Z-W-bromobenzenes and appropriate cycloalkenones after

prepared above.

J3-L2-Bengyloxy-4 - (2- (5-phenylpentyloxy)) phenyl! -cyclohexanone in the form of oil (3.6 g, 87 %) of 2-benzyloxy-4-C2- (5-phenylpentyloxy) 3-bromobenzene (4.0 g, 9.4 mmol).

PIiR: ^ jF ^ 1.10 (d, J = 6Hz, methyl), 3.30 (m, benzylmethine) 4.25 (m, side chain methine), 4.93 (s, benzylethermethylene), 6.30 (dd, J = 8 and 2 Hz, ArH). 6.37 (bs, ArH), 6.88 (d, J =

8 Hz, ArH), 7.23 (s, PhH) and 7.38 (bs, PhH).

IR: (CHCl ₃ ), 1712, 1616 and 1592 cm ^-1 MS: m / e 422 (M ⁺ ), 351, 333, 296, 278, 253, 205 and 91.

xy - 4- · (Ij 1 -dime-thylheptylj.phenylj ~ 4-methyl ~

pyc lohexanon as an oil (5.11 g, 61%) of 2-benzyloxy · 4 ~ (1,1-dimethylheptyl) bromobenzene (7.83 g, 0.0201 mol) and 4-Methyl-cyclohex-2-enone ( 2.21 g, 0.0201 mol).

PMR: C 1 Cl, 0.81 (d, J = 7 Hz, C-4-methyl), 1.28 (s, like.

Dimethyl), 5 ', Ο6 (s, benzylethermethylene), 6.8 - 7.2 (m, ArH)

and 7.35 (s, PhH).

IR: (CHCl ₃ ) 1712, 1613 and 1575 cm ^-1 .

MS: m / e 420 (IvI ⁺ ), 363, 335 _S 329, 273, 271 and 91.

3-C2-Benzyloxy -4- (1,1-d- imethylheptyl) phenyl !? cyclopentanone in the form of an oil (3.5 g, 58 %) of 2-benzyloxy-4- (1 _f 1-dimethylheptyl) bromobenzene (6.00 g, 15.4 mmol); Rf = 0.43 (0.25 mm silica gel, eluted with 1: 1 ~ mixture of ether and hexane).

3-L-2 B eIiZyI oxy-4- (1,1-dimethylheptyl) phenyl o J y cl pheptanon in the form of a .Öls (2.94 g, 46%) of 2-benzyloxy-4- (1,1- dimethylheptylbromobenzene (6.00g, 15.4mol, of oil) and cycloheptenone (1.69g, 15.4mmol).

ßJj ^ j ^ JlJjjpj in the form of a solid (17.9 g, 40%), mp 108-109 ⁰ G, 1-bromo-2,4-dibenzyloxybenzol (43 g, 0.116 mol) and cyclohex-r-2- enone (11.1 g, 0.116 mol). The product vmrde recrystallized from ether-pentane.

Bffi: "cßGl ¹ » ⁴⁷ " ² » ^{8 (m} > ^Meth ylene), 3.37 (bm, benzylmethine), 4.98 ^ (3, benzylethermethylene), 6.47 (dd, J = 8 and

2 Hz, ArH) 6.53 (bs, cf 6.47, ArH), 6.99 (d, J = 8 Hz,

ArH) and 7.31 (s, PhH). IR: (CHCL ₃ ) 1709, 1618 and 1595 cm * " ¹ .

MS: m / e 295, 181 and 91.

Analysis: Calculated for ^c ₂ g ^H 26 ° 3 ^{: Cj 80} » ⁸⁰ » ^H ' ⁶ » ⁷⁸ ^ ⁰ the: C, 80.88; H, 6.80 %.

β-C2-Benzyloxy " 4- (1,1- dimethyloctyl) -phenyl cyclohexanone in the form of an oil (5.0 g, 46 %) of 2 - [, 3-benzyloxy-4-bromophenyl) 2-methylnonane (10 , 4 g, 0.0258 mol) and 2-cyclohexene-i-one (2.48 g, 0.0258 mol).

PMR: ^ ™, 0.83 (m, terminal side chain methyl), 1.23 (s, according to dimethyl), 3.4 (m, benzylmethine), 5.11 (s, benzylethermethylene) _s 6.92 (i.e. , J = 8 and 2 Hz, ArH), 6.92 (d, 'J = 2 Hz, ArH), 7.17 (d, J = 8 Hz, ArH) and 7.42 (bs, PhH)

IR: (CHCl ₃ ) 1715, 1618 and 1577 cm ^-1

MS: m / e 420 (M ⁺ ), 377, 329 and 321 *

3 ~ j ~ 2 ~ benzyloxy ~ ^ in the form of a

oil (27.6 g, 58 %). of 2 - (3-benzyloxy-4-bromophenyl) -2-methylpropane (45.4 g, 0.142 mol) and 2-cyclohexene-i-one (13 * 9 g,

0.145 moles).

PMR: <i ™ ci ¹ » ^{31 (s} » tB ^ y ¹ ) »5,10 (s, benzylethermethylene)

and 6.8-7-4 (m, ArH and PhH).

IR: (CHCl ₃₎ 1724, 1623 and 1582 cm "^'1.

MS: 336 (M ⁺ ), 321, 293, 245 and 91.

}, cyclohexanone in the form of an oil (15.8 g, 63 %) of 2-3 ~ benzyloxy-4-bromophenyl) 2-methylbutane (24.0 g, 0.0721 mol) and 2-cyclohexen-1-one (7.06 g, 0.0735 mol).

PMR: / ™, 0.67 (t, J = 7Hz, terminal it methyl), 1.23 (s, according to dimethyl), 5.10 (s, benzylethermethylene), 6.92 (d ,.

J = 2 Hz, ArH), 6.92 (dd, J = 8 and 2 Hz, ArH), 7 »17 (d,

Jβ 8 Hz, ArH) and 7.42 (bs, PhH).

IR: (CHCl3) 1718, 1618 and 1575 cm ^-1 .

MS: M / e 350 (M +), 335, 321, 307, 259 and 91 ·

3 "f2-Ben zyloxy ~ 4" ^ 1 _i; 1-dimethylbutyl) -phenyl? cy clohe xanon in the form of an oil (15.1 g, 42 %) of 2- (3-benzyloxy-4-bromophenyl) -2-methylpentane (34.8 g, 0.100KoI) and 2-cyclohexene-1 on (10.5 g, 0.110 mol).

PItIR: d ^ SS-, 0.80 (m, terminally methyl), 1.22 (s, according to dimethyl), 5.07 (s, benzylethermethylene), 6.86 (d, J = 2 Hz, ArK ) 6.86 (dd, J = 8 and 2 Hz, ArH), 7.08 (d, J = 8 Hz, ArH) and

7.34 (bs, PhH).

IR: (CHCl ₃ ) 1736, 1631 and 1592 cnf ¹ .

MS: m / e 364 (M ⁺ ), 321, 273 and 91 ·

trana-3- r2-benzyloxy-4 - (1, _1-1, -1-, 3 -ethylheptyl) -phenyl ! -4- (2- propenyl) cyclohexanone as an oil (58.3 g, 70 %) of 1- Bromo-2-benzyloxy-4- (1,1-dimethylheptyl) bromobenzene (73.0 g, 0.188 mol) and 4- (2-propenyl) -2-cyclohexen-1-one (25.5 g, 0.188 mol) ,

IR: (CHCl ₃ ) 1712, 1645, 1613 and 1575 cm * " ¹ MS: m / e 446 (M *), 360, 354 and 91.

PMR: cT ^ L 0.82 (m, terminal methyl), 1.23 (s, according to dimethyl), 4.7-5.1 (m, vinyl H), 5.02 ( _s benzylmethine, 5, 3 6.1 (m, vinyl H), 6.79 (d, J = 2 Hz, ArH), 6.82 (dd, J = 8 and 2 Hz, ArH) and 7.0 (d, J = 8 Hz, ArH).

3 ~ C2 ~ benzyloxy-4 ~ (1, 1-dimethylpentylphenyl) cyclohexanone in the form of an oil (11.5 g, 37 %) of 2- (3-benzyloxy-4-bromo-phenyl) -2 ~ methylhexane (29.6 g, 0.0818 mol) and 2-cyclohexyl-1-one

(8.63 g, 0.09 mol).

IR: (CHCl ₃ ) 173Oj 1629 and 1592 cm ^-1 .

MS: m / e 378 (Ii ⁺ ), 335, 321, 287 and 91.

PIiIR: "J ^ (J ₁ 0.82 (m, terminal methyl), 1.23 (s, according to dimethyl), 3.35 (m, benzylmethine), 5.10 (s, benzylmethylene, 6.90 ( dd, J = 8 and 2 Hz, ArH), 6.90 (d, J = 2 Hz, ArH), 7.13 (d ₉ J = 8 Hz, ArH) and 7.38 (Ids, Ph).

in the form of an oil (11.0 g, 35%) of 2- (3-benzyloxy-4-bromophenyl) -2-yl-4-yl-1-yl-1-ylmethyl) phenyl] cyclohjjsa methylheptane (30.2 g, 0.0806 mol) and 2-cyclohexen-1-one (8.5 g, 0.0886 mol)

IR: (CHCl ₃ ) 1715, 1623 and 1585 cm- ¹ MS: m / e 392 (Ii ⁺ ), 348, 321, 301, 259 and 91 PMR: JpQ ₁ 0.81 (m, terminal methyl ), 1, 22 (s, according to dimethyl), 3.2 (m, benzylmethine), 5.08 (s, benzylmethylene), 6.88 (dd, J = 8 and 2 Hz, ArH), 6.88 (d, J = 2Hz, ArH), 7.10 (d, J = 8Hz, ArH) - and 7.37 (bs, ArH).

3- _{[2-benzyloxy-4-} (1 1 _{"-dimethylnonyl?)} Phenyllcyclohexanon as an oil (13.5 g, 43%) of .2- (3-benzyloxy-4" bromophenyl) -2-methyldecan ) 30.5 g, 0.073 mol) and 2-cyclohexen-1-one

(7.71 g, 0.0803 haul).

IR: (GHGl _3). 1715, 1623 and 1582 cm "" ¹ .

MS: m / e 434 (M ⁺ ), 342, 321 and 91.

BÄR: ⁰ QPQ ₁ 0.85 (m, terminal methyl), 1.24 (s, according to dimethyl), 3.4 (m, benzylmethine), 5.09 (s, benzylmethylene), 6.88 (dd, J = 8 and 2 Ha, ArII) ', 6.88 (d, J = 2Hz, ArH), 7.11 (d, J = 8Hz, ArH) and 7.37 (bs, Ph).

J3 ~ C _M 2- _i Bengyloxy- "4 '-. (1_j, 1r ^ J- ^ e thyldecyl) phenyl} cyclohexanone as an oil (7.0 g, 17%) of 2- (3-benzyloxy! 4-bromophenyl) -2-methylundecane (40.0 g, 0.0928 mol) and 2-cyclohexen-1-one (9.8 g,

0.102 mol).

IRi (CH 2 Cl 2) 1715, 1623 and 1585 cm ^-1 .

MS: m / e 448 (M ⁺ ), 321 and 91. ·

PMRi Cf ^ Q ₁ 0.84 (m, terminal methyl), 1.23 (s, according to dimethyl), 3s5 (benzylmethine), 5.02 (s, benzylmethylene), 6.77 (dd, J = 8 and 2 Hz, ArH), 6.77 (d, J - 2 Hz, ArH), 7.13 (d, J = 8 Hz, ArH) and 7.38 (bs, Ph).

R 2-Benzyloxy-4 - (1,1-dimethylundecyl) phenyl 3-cyclohexanone in the form of an oil (11.5 g, 40 %) of 2- (3-benzyloxy-4-bromophenyl) -2-methyldodecane (27.5 g, 0.062 mol) and 2-cyclohexene-1-cn

(6.68 g, 0.0682 mol).

IRi (CHCl3) 1718 »1623 and 1585 cm"" ¹ .

MSi m / e 462 (M ⁺ ), 417, 371, 321 and 91.

PMR: ^ PQ ₁ 0.89 (m, terminal methyl), 1.26 (s, according to dimethyl), ^ 3.4 (m, benzylmethine) ₅ 5.11 (s, benzylmethylene), 6.89 (dd , J = 8 and 2 Hz, ArH), 6.89 (d, J = 2 Hz, ArH), 7.12 (d, J = 8 Hz, ArH) and 7.37 (bs, Ph).

Z1- i-.9-i-diisopropylheptylphenylcyclooctanone in an oil (10.6 g, 63%) of 2- (3-benzyloxy-4-bromourea)

nyl) -2-methyloctane (15 * 0 g, 38.6 ml) and 2-cycloocten-1-one

(4.78 g, 38.6 mLiol)

IR: (CHCl ₃₎ 1715, 1629 and 1587 cm "^'1.

MS: m / e 434 (M ⁺ ), 477, 363, 349, 343, 326 and 91.

PMR: <f "JJ ^ ₁ 0.83 (m, terminal methyl), 3.7 (bm, benzylmethine), 5» 06 (s, benzylmethylene), and 6.7-7 »5 (m, ArH).

Example 2:

A mixture of 19.5 g (0.0468 mol) of 3-I2-benzyloxy-4- (1,1-dimethylheptyl) phenyl "3-cyclohexanone, 12.3 g of sodium bicarbonate, 3" 00 g of 10 % palladium-on-carbon. Catalyst and 250 ml of ethanol were 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 pesticide, the crude product was purified by column chromatography to 280 g silica gel eluting with 20 tigern Athercyclohexan to win a Peststoff. recrystallization from aqueous methanol Peststoffes this 9,1 g (62%) of Titeiproduktes obtained with a melting point of 87 ⁰ C predominantly in the Hemiketalform.

PIiR: ^ j ^ 0.87 (m, terminal methyl), 1.27 (s, according to dimethyl), ^ 1.0-2.2 (various multiplets), 3 »21 (two proton multiples) and 6, 92 (m, ArH).

IR: (KBr) 3226, 1629 and 1580 cm "" ¹ . ^ ₁ (CHCl3) 357T, 3289, 1704, 1623 and 1575 cm '.

MS: m / e 316 (IvI ⁺ ), 298, 273 and 231..

Analysis: Calculated for C ₂₁ H ₃₂ O _2: C, 79.70; H, 10.19 · Found: C, 79.69; H, 9,89.

The above procedure was repeated, but using the appropriate reactants of Example 1 to prepare the following products.

3 "ί4- (1« 1-di methylheptyl) -2-methylcyclohexa-hydroxyphenyl7-3 in the form of non »of an oil (54 · mg, 86%) from 80 mg (0.19 mmol) of 3- [2-benzyloxy 4- (1,1-dimethylheptyl) phenyl] ~ 3-methylcyclohexanone "

IRi (CHCl ₃ ) 3597, 3390, 1623 and 1572 cm ^-1 . MS: m / e 330 (M ⁺ ), 315, 287 and 245.

~ [4- (1 »1-DimethylIjLeptyl) -2-hydroxyphenyll-4 - inethyl ~ (825 mg, 99%) $ melting point 62 to 64 ⁰ C (from

Pentane recrystallized) of trans-3-L2-benzyloxym- (4- (1,1-dimethylheptyl) phenyl] -4-niethylcyclohexanone (1 ₎ 05 g, 2 _s, 50 mSiol).

PLiR: OqPq ₁ 0.84 (m, terminal side chain methyl), 1.28 (s, according to dimethyl) and 6.75-7.2 (m, ArH). IR: (CHCl 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 ^C 22 ^H 34 ° 2 ^{: C>} 9,97; H, 10,37 Found: C, 80.33; H, 10.30

3- £ 4- _i (T, 1-dimethylheptyl) ^ hydroxyphenyl] cyclopentanone (0.54 g, 47%), melting point 61 to 62 ⁰ C (from pentane) of 3-L2-Benzylozy-4- (1, 1-dimethylheptyl) phenyl]] cyclopentanone (1.50 g, 3.83 mmol).

PMR: O ₀ ³ ^ q ₁ 0.88 (m, side chain terminal methyl), 1.29 (s, according to dimethyl) 2.0-3.0 (m, C-2, 4, 5-methylene), 3, 70 (m Benzylmethin _t), 5.90 (s, phenol), 6.82 (bs, O overlaps ^r 6.92 ₅ ArH), 6.92 (dd, J = 8 and 2 Hz, ArH) and 7, 17 (d, J = 8 Hz, ArH).

IR: (ICBr) 3279, 1739 * 1621 and 1577 cm ^-1 . MS: m / e 302 (M ⁺ ), 283, 217, 189, 175 and 161. Analysis: Calculated for C ₂₀ H ₃₀ O ₂ : C, 79.42} H, 10.00. Found: C, 79.65, H, 10.03.

-44V 207 79

3-F4- (1,1-dim e thylh.eptyl) -2-hydrozyphenyl3cycloheptanon (795 mg ₉ 63%), .Schmelzpunkt 78-79 ⁰ C (from pentane) of 3-L2-benzyloxy-4- (1, i-dimethylheptylcycloheptanone (1.60 g, 3.80 mmol).

PMR: Cf ^ Q ₁ 0.84 (m, terminal methyl), 1.25 (s, according to dimethyl), * * 6.80 (bs, overlaps 6.88, ArH), 6.88 (dd, J = 8 and 2 Hz, ArH) and 7.10 (d, J = 8.Hz, ArH). IR: (CHCl ₃ ) 3571, 3289, 1701, 1621, 1605 and 1577 cm ^-1 .MSi m / e 330 (M ⁺ ) and 245.

Analysis: Calculated for ^C 22 ^H 34 ° 2 ^{: G} »""79»95; H, 10.37. Found: C, 79.60; H, 10.33.

Quantitative yield of 3-E2-hydroxy-4- (2- ( 5-phenylpentyloxy)) -penyl-cyclohexanone in the form of an oil of 3-L2-benzyloxy-4- (2- (5-phenylpentyloxy)) -phenyl! Cyclohexanone ( 1.0 g, 2.26 mmol).

PIIR: cf.TM. 1.28 (d, J = 6 Hz, methyl), 2.7 (m, zvi ei methylene), 3.12 (m, benzylmethine), 4.30 (m, side chain methine), 6 , 32 (d, J '= 2 Hz, ArH), 6.32 (dd, J = 8 and 2 Hz, ArH), 6.80 (d, J = 8 Hz, ArH) and 7.18 (s, Ph H). IR: (CHCl) 3571, 3333, H09, 1623, and 1587 cm ^-1 . MS: m / e 352 (M ⁺ ), 206, 188, and 91.

, 3- (2S4-Dihydroxyphenyl) cyclohexanone in the form of a solid (8.5 g, 94 %) t m.p. = 158 ^° C. (from isopropyl ether) of 3- (2,4-dibenzyloxyphenyl) cyclohexanone (16.9 g , 43.7 mmol).

PMR: ^ JffsMso ¹ »3 - 3.5 (various m), 6.1 - 6.8 (various! M, ArH and OH), and 6.93 (d, J = 8 Hz, ArH). IR: (KBr) 3195, 1631 and 1603 cm " ¹

MS: m / e 206 (Ii ⁺ ), 188, 163, 149 and 136. Analysis: Calculated for ^ ₁₂ H ₁₄ O ₃ : C, 69.88; H, 6.84 % · Found: C, 69.94; H, 6.78%.

-45 - 207 7

3 x -1-4- (1 s -dime thymoctyl) ~ 2- ydyroxy- yphenyl- yl- exanone (0.75 % by weight) , of 2.00 g (4.76 mmol) of 3-t2-benzyloxy-4 - (T, 1-dimethyl octyl) phenylj cyclohexanone. Melting point 78 to 80 ^° C (aas pentane) _β

PMR: ί ^^ 3 0.83 (m, terminal side-chain methyl), 1.22 (s, according to dimethyl) and 6.85 (m, ArH), IR: (CHGl ₃ ) 3571, 3333, 1709 (weak) , 1626 and 1577 cm "" ¹ . MS: m / e 330 (M *), 314, 312, 287 and 231.

Analysis: Calculated for ^G ₂ 2 ^H 34 ° 2 ^{: C} > ^ 9,95} H ₅ 10,37 % · Found: C, 79,97 | H, 9.99 %.

3- (4-t "-Butyl-2" hydroxyphenyl) cyclohexanone (4.22 g, 58 %) of 3- (2-benzyloxy-4-t-butylphenyl) cyclohexanone (10.0 g, 0.0298 mol)

Melting point: 177 to 178 ^° C. (from isopropyl ether).

PM: cT ™ | _0-I j 1.25 (s, t-butyl), 6.7-6.9 (m, two ArH)

and 7 _(O2 ^ (d, "J = ⁶ 8 Hz, ArH).

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

MS: m / e 246 (M ⁺ ), 231, 228, 215, 213, 203, 189, 176 and 161 ·

^ -Ε4 -. (1_ 1-Dimeth _/? - lpropyI _i) -2-h ydrp x yphenyl3cyclohex anon (2.52 g _s 45%), 3 ~ \ ß-Benzylox.y-4- ~ Ci, i-dimethylpropyDphenylJlcyclchexanon (7.50 g, 0.0214 mol) · melting point: 165-166 ⁰ C (from isopropyl ether) PMR. tf '^ o ^ r ° ^"6 3 (t, J = 7 Hz, tenninales methyl) , 1.11 (see, according to dimethyl), 6.8 (m, ArH, OH) and 7.10 (d, J = 8 Hz, ArH).

IR: (CHCl) 3636, 3401, 1724 (weak), 1634 and 1587 cm ^-1 . MS: m / e 260 Qt) 242, 231, 217, 213 and 161 · Analysis: Calculated for G ₁₇ H ₂₄ O ₂ : C, 78.42; H, 9.29 %. Found: C, 78.17J H, 9.22 %

-46- 207 79

3 ~~ 4- (1,1-dimethylbutyl ) -hydroxyphenyl ! Cyclohexanone (0.6 g,

11 %) of 3- "L ² *" ^ ^enz yl ^ox: y "4- (i, 1-dimethyrbutyl) phenylcyclohexyl-

xanon (7.00g, 0.0192 MoI).

Melting point: 101 to 102 ^° C. (from isopropyl ether)

PL! R: ^ ™ Q2 0.82 (m, terminal methyl), 1.25 (s, according to dimethyl) and -%, 80 (m, ArH) * '

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

Analysis: Calculated for C ₁₈ H ₂₆ O _2: C, 78.79; H, 9.55 %. Found: C, 78.78; H, 9.21 %.

- ^ - E ^ -O ) 1-thylheptyl) ~ 2- hydroxyphenyll -4-propylcylohexhexej (1.0 g, 76 %) in solution of an oil of trans-3- 2-benzyloxy-4 - (1,1-dimethylheptyl) phenyl -4- (2-propenyl) cyclohexanone (1.65 g, 3.69 mmol).

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

PISR: eT ^ i 0.9 (m, terminal methyls), 1.22 (s, gem Dimethyle.), ³ 6.70 (dd, J = 8 and 2 Hz, ArH), 6.75 (d, J = 2 Hz, ArH) and 6.87 (d, J = 8 Hz, ArII).

3-C4 "(1> 1-Dimethylpentyl) -2-hyaroxyphenylcyclohexanone (4.0 g, 95 %) of 3-L2-benzyloxy-4- (1,1-dimethylpentyl) phenyl-3-cyclohexanone (5.5 g, 0.0146 mol).

Melting point: 124.5 to 125.5 ⁰ C (from pentane) IR: _(CHCl3) 3623, 3378, 1718 (weak), 1634 and 1587 cm ^"1 MS: m / e 288 (Li ^+), 245 and 231 ,

Analysis: Calculated for C ^ H ₂₈ O ₂ : C, 79.12; H, 9.79 %. Found: C, 79.32; H, 9.53 %.

(quantitatively) of 3- [2 "benzyloxy-4- (T, i-dimethylhexy-diphenylcyclo)

hexanone (2.0 g, 5.1 mmol). Melting point: 82-83 ⁰ C. IR: (CHCl ₃₎ 3636, 1634, 1616 and 1585 cm-is ^"1 in / e 302 (M *), 284, 259 and 231st.

r TM ¹ "-? '·

PMR: O CDOi ° ^'82 ^ ^{s> terraina:} i:. ^It methyl), 1.23 (s, gem di ³

CDOi ^> i: y,, methyl), ³ 3.10 (in), 3.55 (m) and 6 ₃ 83 (m, ArH). Analysis: Calculated for ^G 20 ^H 30 ° 2 ^{: G>} 79.42; H, 10.00 %. Found: C, 79.16 $ H, 9.75 % .

^ (2,4

61 %) of 3-Ü2-benzyloxy-4- (1,1-dimethylnonyl) phenylcyclohexene

non (5.0 g, 11.5 mmol).

Melting point: 72 to 73 ^° C.

IR: (CHCl ₃ ) 3650, 34 ¹ 3, 1721 (weak) 1639 and 1595 cm * " ¹ .

HRMS: m / e 344.2691, (M ⁺ , C ₂₃ H ₃₆ O ₂ ), 326.2570 and 301.2168. PMR: rf ^ Fpci ⁰ ^ ^ ^m "" terminal methyl), 1.28 (s, according to dimethyl), ³ 3.10 (m) and 6.85 (m, ArH).

3-E4-X1,1- whore thyldecy l _i) '2-hydrqxyphenylj ^^ (880 mg,

55 %) 1 of 3 ~ L2 ~ benzyloxy-3- (1, i-dimethyldecylphenylcyclohexa)

non (2.0 g, 4.46 mmol). '

Melting point: 78 to 79 ^° C.

IR: (CHCl) 3623, 1629, 1616 and 1587 cm ^-1 .

ERMS m / e 358.2836 (M ^+, C ₉ H, q0 ,,)

PIvIR: ^ c ^ ci ° » ⁸⁸ ^ ^m 'terminal methyl), 1.27 (s, according to dimethyl), 3.15 ³ (m) and 6.85 (m, ArH).

3 C4 (1, 1-dim ethylundecyl) -2-hydrox yphenyl3? Cyclohexanone (1.49 g,

46 %) of 3- [2-benzyloxy-4- (1,1-dimethylundecyl) phenylcyclohexyl-

xanon (4.00 g, 8.66 mmol).

Melting point: 72 to 73 ^° C. IR: (KBr) 3268, 1629 and 1580 cm ^-1 .

MS: m / e 372 (M ⁺ ), 354, 329 and 231.

^ _{1 Oj87} ( _raj terminal methyl), 1,24 (a, according to dimethyl), 3, 6 (m), 3,42 (m) and 6,88 (m, ArH). Analysis: Calculated for ^c ₂ 5 ^H 40 ° 2 ^{: C> 80} >59; .H, 10.82 %. Found: C, 80.70; H, 10.84 %,

J3-L4 (1: 1 1-Dimethylheptvl) ~ 2-hydrpxyphenyllcyclooctanon (1.92 g, 81%) of 3-L2 ~ benzyloxy-4- (i, 1-dimethylheptyl) phenyllcyclooctanon (3.02 g, 6.95 mmol)

Melting point: 18.1 ⁰ C.

IR: (CHCl ₃₎ 3623, 3356, 1709, 1629 and 1587 cm * ^"1, MS: m / e 344 (M ^+), 329, 326, 283, 273, 259 and 241st

PMR: (J ^ q ₁ 0.82 (m, terminalA methyl), 1.27 (s, according to dimethyl), 3.55 ³ (bm, benzylmethine), 6.76 (d, J = 2 Hz, ArH), 6.78 (dd, J = 8 and 2 Hz, ArH) and 7.02 (d, J = 8 Hz, ArH) analysis: Calculated for C ₂₃ H ₃₆ O _2. C, 80.18; H, 10.53%. Found: C, 79.92; H, 10.37 %.

β-4,4- ( 1,1-dimethyl-thyl) -2-hydroxyphenyl- 3,4-methyl-2-cyclohexyl- 1-one (1.15 g, 70%) of 3-L2-benzyloxy-4 - (1,1-dimethylheptyl) phenyl! ^ - methyl ^ -cyclohexene-i-one (2.10 g, 5.02 mmol). Melting point: 111 ⁰ C (from Diiaopropyläther-petroleum ether) IR (CHCl ₃₎ 3534, 3279, 1667, 1623 and 1567 cm ^"1. MS: m / e 328 (Ii ^+), 313 and 243.

PMR: Cf ^ ₁ 0.83 (m, terminal-methyl), 1.10 (d, J-7 Hz, methyl), ³ 1.25 (s, according to dimethyl), 2.6 (m, methylene) , 3.2 (m, methine), 6.32 (Ids, vinyl H), 6.63 (s, OH), 6 _S 9 (m, ArH) and 7.08 Cd, J = 8 Hz, ArH) , , Analysis: Calculated for G ₂₂ H ₃₂ O _2: C, 80.44; H, 9.83 %. Found: C, 80.35; H, 9.67 %,

Example 3: cis ~ 3 "E2" Benzyloxy-4- (1> 1-dimethylheptyl) phenylcyclohexaIiol

js-l somere

To a -40 ⁰ C solution of 43.0 g (0.106 mole) of 3- [2 ~ benzyloxy ~ 4 ~ (1,1 ~ dimethylheptyl) phenyIjcyclohexanon in 500 ml of methanol and 8.05 g 15'ml tetrahydrofuran were added in three portions (O _s 212 mol) of sodium borohydride. The reaction mixture was stirred at -40 ⁰ C for one hour to warm to -10 ⁰ C allowed to stand and then 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-cyclohexane to give, in the order of elution, 5.0 g (12 %) of trienyl 3- (2-benzyloxy-4- (1.1 dimethylheptyl) phenyl} cyclohexano3.

PMR: < fTM ^ 0.85 (m, terminal methyl), '1.26 (s, according to dimethyl), 3.51 ^ (m, benzylmethine), 4.24 (m, carbinolmethine), 5.15 (s, benzylmethylene), 6.85-7.26 (m, ArH) and 7.47 (m, PhH). IR: (CHCl ₃ ) 3636, 3497, 1629 and 1587 cm ^-1 . MS: m / e 408 (IyI ⁺ ), 393, 390, 323 and 91.

Analysis: Calculated for Cp ₈ H ₄₀ O ₂ : C, 82.30; H, 9.87%. Found: C, 81.98; H, 9.82 % ~.

and 22.2 g (51%) of cis-3- {2-benzyloxy-4- (1,1-dimethylheptyl) -phenyl] -cyclohexanol.

PMR: CiJpQ ₁ 0.85 (m, terminal methyl), 1.28 (s, according to dimethyl), 3.1 (m, benäylmethine), 3.79 (m, carbinolmethine), 5.12 (s, benzylmethylene ), 6.83-7.22 (m, ArH) and 7.42 (s, PhH). Melting point: 75.5 to 76.5 C ⁰

IR: (CHCl) 3636, 3497, 1629 and 1587 cm ** ¹ . MS: m / e 408 (IvI ⁺ ), 393 ,. 390, 323 and 91. Analysis: Calculated for C ₂ 8 ^H 40 ° 2 ^{: C} » ⁸² » ³ ° 5 ^H » ⁹ » ⁸⁷ ^ Found:

C, 81.95} H, 9.74 %.

The following compounds were similarly prepared from appropriate ketones of Example 1

A quantitative yield of Z-3- [2-benzyloxy-4 ~ (1,1-dimethylheptyl ) phenyl} -3- methylcyclohexylamine in the form of an oil of 3- [2 ~?

Benzyloxy-4- (1,1-dimethylheptyl) phenyl} -3-niethycyclohexanone (200mg, 0.476mmol).

PMR: cf.TM. 0.81 (m, terminal side-chain methyl), 1.23 (s, according to dimethyl), 1.30 (s, C-3-methyl), 3.65 (m, carbinolmethine), 5, 00 (s, benzylethermethylene), 6.6-7.3 (m, ArH) and 7.25 (m,

IR: (CHCl ₃ ) 3546, 3378, 1603 and 1555 cm ^-1 .

MS: m / e 422 (IvI ⁺ ) 337, 314, 299, 271 and 229.

trans, trans-3-2-benzyloxy -4- (1,1-dimethylheptyl) phenyl -4- methylcyclohexanol. (0.225 g, 14%) as an oil and 1.19 g (74 ⁰ Io) of the ice, trans-isomers of trans-3-dimethyl), 3.41 (m, Benzylmethin), 4.10 (m, Carbinol methine), 5.17 (s, benzylmethylene), 6.8-7 _S 2 (m, ArH), 7.18 (d, J = 8Hz, ArH) and 7.45 (bs,

IR: (CHCl ₃ ) 3534, 3390, 1613 and 1572 cm ^-1 .

MS: m / e 422 (ii), 337, 331, 314, 246, 229 and 91.

cAg-jj "2-Benzyloxy-4- (2-5-phenylpentyloxy) phenyl] cyclohexanol (1.51 g, 76 %) and the trans isomer (0.379 g, 19 %) in the form of oils of 3-10 2-Benzyloxy-4- (2- (5-phenylpentyloxy)) phenyl] -

cyclohexanone (2.0 g, 4.52 eMoI).

PIiR: Q ^ c ₁ 1.28 (d, J = 6Hz, methyl), 2.68 (m, benzylmethylene), 3.45 (m, bensylmethine), 4.22 (m, carbinolmethine), 4.30 (m, side chain methine), 5.09 (see benzyl ether methylene),

6.45 (dd, J = 8 and 2 Hz, ArH), 6.55 (bs, ArH), -7.10 (d, J = 8 Hz ₁ -ArH) ₁ 7.25 <s, PhH) and 7.45 (bs, PhH). IR: (GHCl ₃ ) 3571, 3448, 1613 and 1590 cnT ¹ . MS: m / e 444 (M ⁺ ), 298, 280, 190 and 91. ice:

PMRI <^ ci ¹ » ^{25 (Oj J = 6 Hz} » methyl), 3.0 (m, benzylmethine), 3j77 (m, carbinolmethine), 4.38 (m, side chain methine), 5.10 (s, benzyl ether methine) , 6.50 (dd, J = 8 and 2 Hz, ArH), 6.58 (bs, ArH), 7.12 (d, J = S Hz, ArH), 7.32 (s, PhH), and 7 _S 43 (a, PhH). IR: (CHGl) 3571, 3390, 1613 and 1587 cm ^-1 . MS: m / e 444 (M ⁺ ), 298, 190 and 91.

3-L2-benzyloxy- 4- (1,1-d in the thylocyl) phenyllecylhexanol (1.35 g, 45 %) and the trans isomer (0.34 g, 11 %) of 3.00 g ( 7.14 μmol) of 3- [2-benzyloxy-4- (1,1-dimethyloctyl) phenyl] cyclohexanone and 0.90 g (30%) of a cis-trans mixture. trans:

PiIR: ο ^ ₁ 0.87 (m, terminal side-chain methyl), 1.25 (s, according to dimethyl), 3.50 (m, benzylmethine), 4.22 (m, carbinolmethine), 5.15 (s, Benzyl at he rm ethyl en) and 6.8-7.6 (m, ArII and PhH).

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

YMR: ό'Qi 0.85 (m, terminal side-chain methyl ) 1.25 (s, according to dimethyl), 3.10 (m, benzylmethine), 3.75 (m, carbinolmethine), 5.12 (s, Benzyl ether), 6.91 (dd ₄ J = 8 and 2 Hs, ArH), 6.91 (d, J = 2.Hz, ArIi), 7.17 (d, J = 8Hz, ArH) and 7, 42 (bs, PIiH).

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

cis -3- (2-benzyloxy) -4-t-butylphenyl) cyclohexanol (7.18 g, 59 %) and the trans isomer (1.33 g, 11 %) and 1.5 g (12 %) of a

mixture of ice and trans isomers from 12.0 g (0.0357 mol)

3- (2 ~ benzyloxy ~ 4 - t-butylphenyl) cyclohexanone.

Melting point: 78 to 79 ^° C. (from hexane)

PME: 0 ^ pQ ₁ 1.30 (s, t-butyl), 3.10 (m, benzylmethine), 3.72

(m, carbinolmethine), 5.12 (s, benzylethermethylene), 6.97 (d,

J = 2 Hz, ArH), 6.97 (dd, J = 8 and 2 Hz, ArH), 7.17 (d, J = 8 Hs, ArH) and 7.40 (bs, PhH).

IR: (CHCl ₃ ) 3636, 3472, 1621 and 1582 cm ^-1 . MSi m / e 338 (M ⁺ ), 323, 320, 230, 215 and 91 ♦ Analysis: Calculated for C ₂₃ Ho ₀ O ₂ : C, 81.61; H, 8.93 % · Found: C, 81.79, H, 8.77 %.

trans:

PMR: Cf ^ Q ₁ 1.23 (s, t-butyl), 3.50 (m .. Benzylmethin), 4.20 (m, Carbinoimethin), 5.02 (s, Benzyläthermethylen) and 6.8 -

7.4 (m, ArH and PhH).

IR: (CHCl ₃ ) 3650, 3472, 1626 and 1587 cm ^-1

MS: m / e 338 (Li ⁺ ), 323, 320, 230 and 91.

ice -3, - L 2 -Benzyl oxy-4- (111 -imethylpropyl) phenyljplo xanol (6.3 g, 78 %) and the, trans isomers (.1.0 g, 12 %) in the form of oils 8.0 g (0.0229 mole) of 3- £ 2-benzyloxy-4- (1,1-dimethylpropyl) phenyljcyclohexanon "ice:

PMR: ^^ q ₁ 0.67 (t, J = 7 Hz, terminal methyl), 1.26 (s, according to dimethyl), 3.05 (m, benzylmethine), 3.75 (m, carbinoimethine), 5.15 (s, Benzyläthermethylen), 6.92 (d, J = 2 Hz, ArH) ₅ 6.92 (dd, J = 8 and 2 Hz, ArH), 7.17 _(s d J = 8 Hz, ArH), and 7.42 (bs, PhH) _e IR: (CHCl ₃ ) 3636, 3344, 1626, and 1587 cm ^-1 . MS: m / e 352 (M ⁺ ), 337, 334, 323, 244, 215 and 91. transj

IR: (CHCl ₃ ) 3636, 1626 and 1587 cm ^-1 . MS: m / e 352 (M ⁺ ), 337, 334, 323, 244, 215 and 91.

jg.g-ß .-. i 2-benzyl oxy-4- , (1, 1-d-imidylbityl ) -phenyl , 1-eye-1- hexanol (4.16 g, 52%) and the trans isomer (0.88 g, 11 %) and "0.49 g (6.1 #) of a mixture of cis and trans isomers. " In the form of oils of 8.0 g (0.022 mol) 3- [2-Benzylöxy-4- (1,1-dimethyl-

"butyl) phenyl] cyclohexanone"

PMR: Oc DGl °, ⁸⁰ ( ^m > terminal methyl), 1.23 (s, according to dimethyl), 3, O5 ^ (m, benzyl), 3.70 (m, Carbinolmet.hin), 5.08 ( s, benzylethermethylene), 6.86 (d, J = 2Hz, ArH), 6.86 (dd, J = 8 and 2Hz, ArH), 7.11 (d, J = 8Hz, ArH), and 7 , 35 PhH).

IR: (CHCl ₃ ) 3623, 3448, 1621 and 1582 cm ^-1 . MS: m / e 366 (M ⁺ ), 351, 348, 323, 258, 215 and 91. trans:

PMR: (? ° ^Q 3 ( ^m terminal terminal methyl), 1.22 (s, according to dimethyl), 3.40 (m, benzyl methine), 4.18 (m, carbinol methine), 5, 09 (s, benzylethermethylene), 6.86 (d, J = 2Hz, ArH), 6.86 (dd, J = 8 and 2Hz, ArH), 7.11 (d, J = 8Hz, ArII ) and 7.39 (m, PhH).

IR: (CIICl) 3623, 3472, 1623 and 1585 cm ^-1 . MS: m / e 366 (M ⁺ ), 351, 348, 323, 258, 215 and 91 ·

trans-3-C 2- benzyloxy-4 "(151 -dimethylheptyl) -phenyl-4- (2-

(1.9 g, 13 %) and the oil is trans-4-

Isomers (7.3 g, 51 %) in the form of oils of trans -3-benzyloxy-4- (1,1-dimethylheptyl) phenyl -4- (2-propenyl) cyclohexanone (14.3 g, 32.1 mmol). Sequence of elution on silica gel with a 2: 1 mixture of pentane and ether gave the trans-3 _s cis-4 isomer of the title compound in the form of an oil followed by the cis-3, trans-4-isomer.

IR: (CHCi ₃ ) 3559, 3401, 1639, 1608 and 1567 cm MS: m / e 448 (M ⁺ ), 433, 430, 363, 406 and 91.

" ¹

PHR: «ί ™ _Ί 0.82 (m, terminal methyl), 1.25 (s, corresponding to

methyl), 3.30 (m, benzylmethine), 4.12 (m, carbinolmethine), 4.6-5.0 (m, vinyl H), 5.06 (a, benzylmethylene), 5.2-6, 1 (m, vinyl H), 6.82 (d, J = 2 Hz, ArH), 6.82 (dd, J = 8 and 2 Hz, ArH), 7.07 (d, J = 8 Hz, ArH ) and 7,38 (bs, Ph). 015, -3 » trans-4-isomer:. , ~

IR: (CHGl ₃ ) 3571, 3401, 1639, 1610 and 1572 cm ^-1 . MS: m / e 448 (M ⁺ ), 406, 3 * 63 and 91.

PMR: ^^ - ^ 0.82 (m, terminal methyl), 1.2.2 (s, according to dimethyl), 2, Io (m, benzylmethine) j 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, ArH), 6.75 (d , J = 8 and 2 Hz, ArH), 6.99 (d, J = 8 Hz, ArH), and 7.25 (bs, Ph).

cis-β- 2-benzyloxy-4- (1> 1- dimethylhexyl) phenyl! - ^ ft butenyl) cyclohexanol (495 mg, 82 %) , and the trans-3 * cis-4 isomer (105 mg, 18%) of trans -3- [benzyloxy-4- (1,1-dimethylheptyl ) phenyl] -2-butenylcyclohexanone (600 mg, 1.3 mol%).

The trans-3, cis -4 isomer was first eluted trans-3 cis 4-isomer:

MS: m / e 462 (M ⁺ ), 447, 444, 377 and 91.

cis-3 1 trans-4 isomeres_

IRi (CHCl ₃ ) 3610, 3448, 1618 and 1577 cm ^-1 .

MS: m / e 462 (M ⁺ ), 447, 444, 377 and 91.

cis-.beta .- [2-Benzyls: y-4 "'(1'-1-dimethoxy ) heptyl) phen yl1 -trans-4 - ( _2-pentanyl) cyclohezime and the trans-3, cis-4 isomer of trans-3- (2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl) -4- (2-pentenyl) cyclohexanone (497 g, 1.04 mmol). 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 _s trans ~ 4 isomer (Rf = 0.13, silica gel , 33 % ether-pentane).

(5.0 g, 83 %) and the trans isomer (0.60 g, 10%) in the form of

Oil 3- (2-Benzyloxy-4- (1,1-dimethylpentyl) phenyl] cyclohexanone (6.0 g, 58 mmol). , trans:

IR: (CHCl ₃ ) 3636, 3497, 1623 and 1582 cm ^-1 . "MS: m / e 380

PMR: ^ JJo ₁ 0.83 (m, terminal methyl), 1.24 (s, according to dimethyl), 3j5 (m, benzylmethine), 4 _} 20 (m, carbinolmethine), 5 _s O9 (s, benzylinethylene) and 6.8-7.6 (m, ArH). ice:

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

PMR: JPtJq ₁ 0.75; (m, terminal methyl), 1.14 (s, according to dimethyl), 2.9 O ³ Cm, benzylmethine), 3.52 (m, carbinolmethine), 4.80 cs, benzylmethylene), 6.49 (dd , J = 8 and 2 Hz, ArH), 6.49 (d, J = 2 Hz, ArH), 6.72 (d, J = 8 Hz, ArH) and 6.96 (bs, Ph).

cUa-3 ~ I-2-Benzyl OXy - ^ - (I- _1- y-yylyloxy) (3.0 g, 43 %) and the _tran s-isomer (660 mg, 9 %) in the form of oils of 3-l2-benzyloxy - ~ 4- (1,1-dimethylhexyl) phenyl] cyclohexanone (7.0 g, 17.9 mmol)

ice:

IR: (CHCl ₃ ) 3623, 3448, 1618 and 1575 cm ^-1 × MS: m / e 394 (M ⁺ )

PMR: CTqJJc ₁ 0.82. (m, terminal methyl) 1.22 Cs, acc. Dimethyl), 3.07 (m, benzylmethine), 3.70 (m, carbinolmethine), 5.08 (s, bensylmethylene), 6.88 (dd, J = 8 and 2 Hz, ArH), 6.88 ( d, J = 2 Hs, ArH), 7.12 (d, J = 8 Hz, ArH) and 7.37 (fs, Ph). trans:

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

PIiIR: 6 ¹ ^ q -j. 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).

cis-β- E2-benzyloxy-4 "- (1", 1-dimethylnonyl) -phenyl-3-cyclohexanol (5jO g, 59 %) and the trans isomer (1.0 g, 2%) in the form of.

Oils of 3-L2-benzyloxy-4- (1,1-dimethylnonyl) phenylcyclohexa

non (8.5 g, 19.6 mmol).

ice: . '

IR: (CHCl ₃ ) 3623, 3448, 1618 and 1577 cm ^-1 .

MS: m / e 436 (M ⁺ )

i ff ^ ₁ 0.83 (m, terminal methyl), 1.22 (s, according to dimethyl), ^ 3.04 (m, benzylmethine, 3.67 (m, carbinolmethine, 5.08 (s, benzylmethylene) , 6.87 (dd, J = 8 and 2, Hz, ArH), 6.87 (d, J = 2 Hz, ArH) and 7.05-7.45 (m, ArH and Ph) * tra ns:

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

TMR: (Tj ^ ₁ 0.82 (m, terminal methyl), 1.22 (s, according to Di

j ^ ₁

methyl), 3 3 ^ 2 ( _m> benzylmethine), 4.16 (m, carbinolmethine), 5.02 (s, benzylmethylene) and 6.7-7.5 (m, ArH and Ph).

cis-3C2-Benzyloxy-4- ( 1,1-dimethylundecyl) -phenyl] -cyclohexanol (3.5 g »50 %) and the trans isomer (1.0 g, 14%. in the form of oils of 3- [2 -Benzyloxy-4- (1,1-dimethylundecyldhenylcyclohexanone (7.00 g, 15.0 mmol).

IR: (CHCl) 3636, 3448, 1621 and 1582 cm ^-1 MS: m / e 464 (M ⁺ ).

PIiR: Cf ^ Q ₁ . 0.95 (m, terminal methyl), 1.33 (s, according to dimethyl), 3.09 ² ^, benzylmethine), 3.70 (m, carbinolmethine), 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, ArH) and 7.50 (Tds , PhH).

iJä £ §JL

IR (CH 2 Cl 2) 3534 (wide), 1618 and 1577 cm ^-1 .

MS: m / e 464 (M ⁺ )

PMR: ^ J) CE ₁ 0.85 (m, terminal methyl), 1.22 (s, according to Di-3

methyl), 3.48 (m, benzylmethine), 4.17 (m, benzylmethine), 5.08 (s, benzylmethylene) and 6.75-7.55 (m, ArH and Ph).

cis ~ 3 ~ / 2 "'- B.enzyloxy-4- (1, 1-dimethyl-dimethyl) phenyl / cyclohexanol ( 2.66g , 59 %) and the trans isomer (0.36g, 8 %) in the form of oils of 3- / 2-benzyloxy-4- (i, 1-dimethyldecyl) phenyl-7-cyclohexanone (4.5 g, 10.0 mmol).

IR: (CHCl ₃ ) 3704, 3571, 1639 and 1597 cm ^-1 MS: m / e 450 (M ⁺ )

PMR: 0 J ^ ₁ 0.86 (m, terminal methyl), 1.25 (s, according to dimethyl), 3.08 (m, benzylmethine), 3.74 (m, carbinolmethine), 5.08 (s , Benzylmethylene, 6.88 (dd, J = 8 and 2 PIz, ArH), 6.88 (d, J = 2Hz, ArH), 7.12 (d, J = 8Hz, ArH), and 7.37 (bs, Ph).

trans:

IR: (CHCl ₃ ) 3623, 3448, 166, and 1577 cm ^-1 . MS: m / e 450 (M ⁺ )

PMR: cT ^ ₁ 0.82 (m, terminal methyl), 1.22 (s, gem dimethyl.) 3j53 (m, Benzylmethin), 4.22 (m, Carbinolmethin), 5.02 (s, benzylmethylene ) and 6.8-7.6 (m, ArH and Ph).

cis-3/2-benz . yloxy-4- (1,1-dimethylheptyl) phenyl7c7 / 'clooctanol (1> 36 δ »19 %) and the trans isomer (4.12 g, 59 %) in the form of oils of 3- / 2- Benzyloxy-4- (i, 1-dimethylheptyl) phenyl-7-cyclooctanone (7 ₅ o g, 16.1 ml / vol)

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

PIvIRccT Q ^ Jq ₁ 0.83 (m, terminal methyl), 1.28 (s, according to Di-3 '

methyl), 3.19 (bm, benzylmethine), 3.89 (bm, carbinolmethine), 5.10 (s, benzylmethylene), 6.83 (m, ArH), 7.08 (d, J = 8Hz, ArH) and 7.38 (m, Ph). , '

trans:

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

No. f .-. m -i

n id ^ l Π K; if C! }

PMR: Cf (SJ) C ₁ O »83 (m, terminal methyl), 1.28" (s, according to dimethyl), 3.4 bm, b'enzylinethine), 3.9 (m, carbinol methine), 5.10 (s, benzylmethylene), 6.85 (m, ArH), 7.08 (d, J = 8Hz, ArH) and 7.36 (m, Ph).

example

cis -3 C4- { 1,1 -dimethyl hepty -1- yl- hydroxyphenyl] cyclohexanol A mixture of 22.0 g (0.0539 mol) of cis-3 ~ [2-benzyloxy-4- (1,1-dimethylheptyl ) phenyl | cyclohexanol, 12.0 g and 2.0 g of 10% ITatriumhydrogencarbonat PaD.adium-on-charcoal was stirred for 2 hours under an atmosphere of hydrogen "the reaction mixture vmrde with ethylacetate filtered through diatomaceous earth, and the filtrate to a solid evaporated. The Peststoff was recrystallized from hexane to give 13.2 g (77%) of the title product with a melting point 109-110 ⁰ C,

Rffi: Oq ^ ₁ 0.81 (m, terminal methyl), 1.25 (s, according to dimethyl), 2.8o3 (bm, benzylmethine), 3.80 (bra carbinolmethine), 5.4 (broad, OH ), 6.63 (bs, ArH), 6.77 (dd, J = 8 and 2 Hz) and 6.87 (J = 8 Hz, ArH),

IR: (CHCl ₃ ) 3610, 3356, 1626 and 1582 cm ^-1 * MS: m / e 318 (M ⁺ ), 300, 233 and 215.

Analysis: Calculated for C ₂ 1 ^H 34 ° 2 ^{: C> 79} » ¹⁹ > ^H » ^1O »7 ⁶ · Found: C, 78.96; H, 10.59

According to the above procedure, the compounds listed below were prepared from suitable reactants of Example 3.

tr8ü3-3-F4- (1,1-dimethylheptyl) -2-hydrox yphenyll cyclohexanol (2.47 g, 71%), mp 124-125 ⁰ C (from pentane) of trans-3- [2-benzyloxy-4 - (1,1-dimethylheptyl) phenyl! cyclohexanol (4.50 g, 0.011 mol).

PMR: ^^ Gl-0.81 (m, terminal methyl), 1.25 (s, according to Dime

methyl), 3.25 (m, 1-benzylmethine), 4.22 (m, carbinolmethine), 6.81 (d, J = 2Hz, ArH), 6.81 (dd, J = 8 and 2Hz). and "7.08 (d, J = 8 Hz, ArH).

IR: (CHCl) 3610, 3390, 1626 and 1575 cm ^-1 . MS: m / e 318 (M ⁺ ), 300, 233 and 215. Analysis: Calculated for: C ₃₁ H ₃₄ O ₂ : C, 79.19s H, 10, 76. Found: C, 78.82, H, 10.43.

A quantitative yield of Z - 3 - L 4 -. (I ,, 1.-Dime thy Ineρ t yl) ^ j _ ~ hydroxyphenyl] .- 3-me thyl eye l ohexanol, mp 90-91 ⁰ C ( recrystallized from petroleum ether) of Z ~ 3-B> -benzyloxy-4- (1,1-dimethylheptyl) phenyl3-3-methylcyclohexanol) (180 mg, 0.246 mmol).

PMR: O ^ g ₁ 0.85 (m, terminal side-chain methyl), 1.25 (s, gem. ^ Dimethyl), 1.33 (s, C-3-methyl), 3.65 (m »carbinolmethine), 5.48 (bs, OH), 6.63 (d, J = 2Hz, ArH), 6.82 (dd, J = 8 and 2Hz, ArH) and 7.19 (d, 8Hz, ArH) , IR: (CHCl) 3597, 3333, 1605 and 1570 cm "* ^1. MS: (! £ +) m / e 332, 314, 299, 286, 271, 247 and 229. Analysis: Calculated for ^C ₂ ^H 36 2 ° 2 ^{: C> 7} ^, 45; H, 10, 92. Found: C, 79.24, H, 10.64.

' ¹ I

A quantitative yield of _i t rans, trans-3-r4 '".. (1 _l 1?"' -2-h yärox. J he p _Ty l);) rphenyl} - ^ - methyl lcyclo hexanol, mp 134 to 135 ⁰ C (from pentane) of trans, trans-3-benzyloxy-4- L ² C1.j 1-dimethylheptyl) phenyl} -4-methylcyclohexanol (190 mg, 0.450 mmol).

PICR: ^ "" .. ⁰ >? ~ "9 ^ ^m " ^G "" 4- ^{terminal and} terminal side-chain methyls), -1.24 (s, according to dimethyl), 3.00 (m, benzylmethine), 4.22 (m, carbinolmethine), 6.78 ( d, J = 2 Hz, ArH), 6.88 (dd, J = 8 and 2 Hz, ArH) and 7 * 02 (d, J = 8 Ez, ArH). IR: (CHCl ₃ ) 3571, 3333, 1626 and 1575 cm ^-1 . MS: m / e 332 (H ⁺ ) 317, 314, 247, 233 and 229.

Analysis: Calculated for C ₂₉ H ₃₆ O _2: C, 79.46; H, 10.92 %. Found: C _s 79,13; H ₅ 10.68 % [

A quantitative yield of cis, trans-3-J4- (1? 1-dimethylheptyl) - ^ - h ydroxyphenyl! 4-methylcyclohexanol , m.p. 150 "to 151 ^° C, (from pentane), from cis, trans-3-L2-benzyloxy-4- (1,1-dimethyl-2-bis) -phenyl-4-methyl-cyclohexanol (1.15 g , 2.72 mmol).

PMR: t ^ cDCl ° » ^{72 (dj J = 6HZjc} " -4-methyl), 0.86 (m, terra-side-chain methylene), 1.24 (s ₅ according to dimethyl), 2.62 (m, benzylmethine ), 3.77 (m, carbinol methine), 6.70 (d, J = 2 Hz, ArH), 6.83 (ad, J = 8 and 2 Hz, ArH) and 7.04 (d, J = 8 . Hz, ArH) IRi (CHCl ₃₎ 3571, 3333, 1621, I6O5, and 1580 cm "" ^1. MS: m / e 332 (I ^+), 314, 272, 247, 233 and 229 * analysis: Calculated for ^C 22 ^H 36 ° 2 ^{: C> 7} ^, 46; H, 10.92 Found: C, 79.15} H, 10.72.

cis -3- 4- (1,1- dimethylhepto / l) -2-hydros: yphenylcyclopentanol (464 mg, 55 %) and 228 mg (27 %) of trana isomer in the form of oils of a mixture of cis and cis trans -3- (2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl} cyclopentanol (1.10 g, 2.79 mmol).

PMR: ^ JK _n 0.83 (m, side chain terminal methyl), 1.24 (s.

gem. Dimethyl), 3.2 (m, benzylmethine), 4.52 (m, carbinolmethine), 6.75 (dd, J = 8 and 2 Hz, ArH), 6.81 (bs), overlaps c / 6.75,

ArH) and 6.97 (d, J = 8 Hz, ArH). IR: (CHCl ₃ ) 3571, 3300, 1623 and 1567 cm ^-1 .

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

trans:

PMR: <^ ™ _Γ 0.83 (m, side chain terminal methyl), 1.27 (s,

dimethyl, 3.60 (m, benzylmethine), 4.55 (m, carbinolmethine), 6.78 (bs, δ 6.88, ArH), 6.88 (dd, J = 8 and 2 Hz,

ArH) and 7.10 (d, J = 8 Hz, ArH). IR: (CHCl ₃ ) 3571, 3333, 1621 and 1575 cm ^-1 .

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

A quantitative yield of trans-3 - L4 ~ (1 "1-Dirneth ylhe ^ p_- ty _i l) _{i" i} 2 _i "hy _i drp _i xyp _f hcnyllc yclohep _{i i} te _J nol, m.p. 55" to 57 ⁰ C, of tran-s-3 ~ L2-Benzylo2: y-4- (1,1-dimethylheptyl) phenylTcycloheptanol (695 mg, 1.64 mmol).

PMRs O ^r ^ q ₁ 0.88 (m, terminal methyl), 1.22 (s, according to dime, thyl), 3.203 (m, benzylmethine), 4.22 (m, carbinol methine) _s 6.85 ( dd, J = 8 and 2 Hz, ArII), 6.90 (bs, overlaps </ 6.85, ArH) and 7.13 (d, J = 8 Hz, ArH)

IR: (CHCl) 3333, 1621 and 1570 cm ^-1 . MS: m / e 332 (Ii ⁺ ), 314, 247 and 229.

Analysis: Calculated for ^C 22 ^H 36 ° 2 ^{: C} * ^ 9.46} H, 10.92 «Found: C, 79.68; H, 10.62.

A quantitative yield of o ia-3-E4- (1,1-dimethylheptyl ) - ^ -hydroxy- phenyl! C ycloheptanol , m.p. 103-104 ⁰ C (recrystallized from pentane), of ci3-3- [2 ~ benzylose: y-4- (1,1-dimethylheptyl) phenyl-3-cycloheptanol (380 mg, 0.90 mmol).

PMR: cfTM ^ 0.82, (m, terminal methyl), 1.20 (s, according to dimethyl), 3.0 (m, benzylmethine), 4 »0 (m, carbinolmethine), 6.72 (bs , overlaps * Γ6.81, ArH), 6.81 (dd, J = 8 and 2 Hz, ArH) and 7.08 (d, J = 8 Hz, ArH)

IR: (CHCl) 3571, 3311, 1621, 1605 and 1580 cm ^-1 . MS: m / e 332 (M ⁺ ), 314, 247 and 229.

Analysis: Calculated for C ₂ 2 ^H ^ S ° 2 ^{: C> 79} ' ⁴⁶ ' ^H » ¹⁰ » 9 ² . C, 79.39; H, 10.72.

Sine quantitative yield of cis -? - C2 - hydroxy-4- (2- (5-phenylpentyloxy)) phenyl! Cyclohexanol, melting point 80 to 84 C (pentane) of cis-3-C2-benzyloxy-4- (2 ~ (5-phenylpentyloxy) phenyl} cyclohexanol (1.45 g, 3.27 mmol).

PMR: ^ ™ q _X 1.25 (d, J = 6 Hz, methyl), 3.75 (ni, carbinoliethine), ^ 4,20 (m, side chain methynes) _s 6,23 (bs, ArH), 6,40 ( dd, J = 8 and 2 Hz) and 6.98 (d, J = 8 Hz, ArH) and

7.13 (s, PhH).

IR: (CHCl ₃ ) 3597, 3333, 1623 and 1597 cm ^-1 . MS: m / e 354 (M ⁺ ), 336, 208, 190 and 91.

Analysis: Calculated for C ₂₃ H ₃₀ Oy C, 77.93; H, 8.53 %, Found: C, 77.955 H, 8.31%.

Trang-3 "E2" hydroxy-4- (2 - (5-phenylpentylos: y)) phenyllcyclohexanol (241 mgs 90%), melting point 65 to 70 ⁰ C (pentane) of trans-3- £ 2-benzyloxy-4 - (2- (5-phenylpentyloxy)) phenylcyclohexanol (0.355 g, 0.754 mmol).

PMR: cTöDC! 1.25 (d, J = 6Hz, side chain methyl), 4.13 (m, carbinol and side chain methines), 6 _$ 26 (d, J = 2Hz, ArH), 6.26 (dd, J = 8 and 2 Hz, ArH), 6.82 (d, J = 8 Hz, ArH) and 7.05 (s, PhH).

IR: (CHCl ₃ ) 3597, 3378, 1629, and 1587 cm ^-1 . MS: m / e 354 (M ⁺ ), 336, 208, 190, and 91.

Analysis: Calculated for C ₂₃ H ₃₀ O _3: C, 77.93; H, 8.53 % · Found: C, 77.53; H, .8.40 %.

cis- 3 "4- (1,1-Simethyloctyl) -2-h ydrozyphenyl cyc lohexanol (0.725 g, 68%) from 1.36 g (3.22 mmol) of cis-3-t2-benzyloxy-4 (1 1-dimethyloctyl) phenyl] cyclohexanol Melting point: 100 to 101 ^° C. (recrystallized from hexane).

PMR: [alpha] ⁸² ( ^m > terminal side chain methyl), 1.22 (s ₃ according to dimethyl), 2.90 (m, benzylmethine), 3.12 (bs, OH), 3.70 (m, Carbinol methine), 6.62 (d, J = 2 Hz, ArH), 6.75 (dd,

J = 8 and 2 Hs, ArH) and 7.00 (d, J = 8 Hz, ArH). IR: (CHCl ₃ ) 3571, 3333, 1626 and 1582 cm ^-1 . MS: m / e 332 (M ⁺ ). 314, 233 and 215.

Analysis: Calculated for C ₂ 2 ^H 36 ° 2 ^{: G} »79» 46 »H, 10.92 %. Found: C, 79.85; H, 11.03 %.

trans-3-C4 ~ (1,1-I) IInet hyloctyl) - ^2-hYdi> oxyp nenyllcyclohexanol * (0.195 g, 100%) (in the form of an oil from 246 mg 0.582 mmol) of trans-3- [2-benzyloxy -4- (1,1-dimethyloctyl) phenyl] cyclohexanol. Melting point: 94-95 ⁰ C (aas petroleum ether)

^ Q ₁ 0.82 (m, terminal side chain methyl) ₅ 1.24 (s, according to dimethyl), 3.28 (m, benzylmethine), 4.20 (m, carbinolmethine and OH) ₉ 6.83 (dd, J = 8 and 2 Hz, ArH), 6.83 (d, J ^ 2 Hz, ArH) and 7.10 (d, J = 8 Hz ₁ ArH)

IRi (CHCl ₃ ), 3650, 3436, 1639 and 1582 cm ^-1 . MS: m / e 332 (Ii ⁺ ), 314, 233 and 215.

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

Cls-3- (4-t-butyl-2-hydroxyphenyl) cyclohexanol (3.99 g, 77 %) of cis -3- (2-benzyloxy-4-t-butylphenyl) cyclohexanoi (7 »1 g, 0.021 moles)

Melting point: 177 to 178 ⁰ C (aas isopropyl ether).

Plffi: ^ ₁ 1.23 (s, t-butyl), 2.88 (m, benzylmethine), 3.55 (m, carbinolmethine), 6.75 (m, two ArH) and 6.92 (d, J = 8 Hz, 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 ^ ⁰ K ₂₅ O ₂ : C, 77.37; H, 9.74 %. Found: C, 77.00, H, 9.54%.

T raris-3- (4-t-3-butyl-2-hydroxyphenyl ) cyclohexanol (0.725 g, 99 %) of trans-3- (2-benzyloxy-4-t-butylphenyl) cyclohexanol (1.25 g, 2, 96.mMol)

Melting point: 136 to 137 ^° C (aas isopropyl ether).

PMR: cf ™ Gl ^{1> 2T} (s »tB ^ yD» 3.35 (m, benzylmethine), 4.32

, - Carbinoimethine), 6.95 (d, J = 2 Hz, ArH), 6.96 (dd, J = 8 and 2 Hz, ArH) and 7.15 (d, J = 8 Hz, ArH). IR: (CHOI.) 3623, 3401, 1626 and 1575 cm " ¹ ..

207 799

MS: m / e 248 (M ⁺ ), 233, 230, 215, 187 and 173.

Analysis: Calculated for ⁰ ^ H ₃₄ O ₂ : C, 77.37; H, 9.74 %. Gefun- '

the: C, 77.34; H, 9.49 %. ,

cia-3- [4- (1 -Dimethyl-dimethyl) -2-hydroxyphenyll cyclohexanol (1.45 gj 32%) of cis -3-benzyloxy-4- (1,1-dimethylpropyl) phenyl] cyclohexanol (6.1 g, 0.0173 mol). Melting point: 166-167 ⁰ C (from isopropyl ether) · PMR: '<fJvJxJ _{1 "DM} SO-D ⁶⁵ ° ^{(t' J = 7 Hz" te2: minales} methyl), 1.20 (s, like "Dirnetnyl.) , 2.91 (m, benzylmethine), 3.62 (m, carbinolmethine), 6.75 (m, two ArH), 7.02 (d, J = 8Hz, ArH) and 7.55 (a, OH ).

IR: (KBr) 3509, 3279, 1629 and 1592 cm "" ¹ .

MS: m / e 262 (M ⁺ ), 247, 244, 233 and 215..

t rans-3-L4- (1,1-Dirnethylprop yl) -2-hydroxyphen yl] cyclohexanol (0.50 g, 68%) of trans-3-· L2-benzyloxy-4 '(1,1-dimethylpropyl) phenyl 3-cyclohexanol (1.00 g, 2.84 mmol).

Melting point: 124 to 125 ^° C. (from isopropyl ether).

PMR: (T ^ q ₁ 0.67 (t, J = 7 Hz, terminal methyl), 1.23 (according to dimethylnyl), 3.30 (m, benzylmethine), 4.05 (m, carbinolmethine) , 6.76 (m, two ArH) and 6.93 (d, J = 8 Hz, ArH). IR: (CHGl ₃ ) 3636, 3413, 1639 and 1585 cm ^-1 . MS: m / e 262 ( M ⁺ ), 247, 244, 233 and 215.

Analysis: Calculated for ⁰ ^ H ₂₆ O ₂ : C, 77.82; H, 9.99 %. Found: C, 77.51; H, 9.87 %. '

cis-3 - [, 4- (1,1-methylthylbutyl) -2-hyroxystyrene ] 3-cyclohexanol (1.9 g, 74 %) of cis-3-L2-benzyloxy-4-4 (1, 1-dimethylbutyD-phenyl] cyclohexanol (3.39 g, 9.26 mmol). melting point: 138-139 ⁰ C (from pentane).

PMR: ⁰ CPQ ₁ 0.82 (m, terminal methyl), 1.25 cs, acc. Dimethyl), ³ 2.90 cm ₁ benzylmethine), 3.78 (m, carbinol methine), 6.8 (m, ArE) and 7.11 (d, J = 8 Hz, ArH)

IR: (ICBr) 3509, 3279, 1629 and 1592 cm ^-1

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

(0.45 g, 87 %) in the form of an oil of trans-3 ~ 2 ~ benzyloxy-4- (1,1-dimethylbutyl) phenyl] cyclohexanol (0.700 g, 1.91 mmol).

j- fra / rQ

PMR: V-VQC ₁ ° '80 ^(m »" fce ^ inales methyl), 1.22 (s, according to dimethyl), 3, 15 (m, benzylmethine), 4.22 (m, carbinolmethine), 6, 81 (d, J = 2 Hz, ArH), 6.81 (dd, J = 8 and 2 Hz, ArH) and 7.06 (d, J = 8 Hz, ArH).

IR: (CHCl ₃ ) 3636, 3390, 1629 and 1575 cm ^-1 . MS: m / e 276 (Ii ⁺ ), 261, 258, 233 and 215.

trans-3-C1,1 -L4-D imethylheptyl) - ^ - hydroxyphenyl] pylcycloh exanol (626 mg, 78%) of trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyIl-cis- 4- (2-propenyl) cyclohexanol (1.0 g, 2.23 mmol)

Melting point: 92 to 94 ^° C.

3PMR: CT ^ q ₁ 0.85 (m, terminal methyls), 1.25 (s, according to dimethyl), 3 3 ₉ o5 (m, benzylmethine), 4.22 (m, carbinolmethine), 6.55 - 6.9 (m, ArH) and 7.01 (d, J = 8 Hz, ArH)

IR: (CHCl) 3623, 3390, 1629 and 1578 cm ^-1 .

Analysis: Calculated for ° ₂ 4 ^Η 4ο ^Ο 2 ^{: C} » ⁷ ^, 94; H, 11.18 %. Found: C, 80.10; H ₉ 10.89 %.

CJ3-3- 4- (1,1-Dimethylheptyl ) -2-hydroxyphenyl-trana- 4-propylcyclohexanol (550 mg, 74 %) of cis -3-f2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -trans-4 ~ (2-propenyl) cyclohexanol (930

mg, 2.07 mmol).

Melting point: 126 ⁰ C (aas P.entan). IR: (CHCl ₃ ) 3597 *, 3390, 1629 and 1575 cm ^-1

MS: m / e 360 (M ⁺ ), 345, 342, 275 and 257.

PMRS ⁰ ° CDCl ^{'82 (mj} "fcerain & le töethyle), · 1.27 (s, gem. Dimethyl), ³ 2.65 (m, Benzylmethin), 3.75 (m, Carbinolmethin), 6.75 (m, ArH) and 7.07 (d, J = 8 Hz, ArH).

Analysis: Calculated for C ₂₄ H ₄₀ O _2: C, 79.94; H, 11.18 %. Found: C, 79.85; H, 10.95 %.

trans-4-butyl-cis -3-L4- (1,1-dimethylheptyl ) -2-hy drozyphenyl-cyclohexanol (322 mg, 80 %) of cis-3-L2-benzyloxy-4- (1,1- dimethylheptyl) phenyl 3 -trans-4- (2-butenyl) cyclohexanol (500 mg _f 1.08 mmol). ,

Melting point: 131 ^° C. (from pentane). IR: (CHCl ₃ ) 3636, 3356, 1629 and 1587 cm ^-1 .

MS: m / e 374 (M ⁺ ), 356, 302, 289, 272, 271, 257, 247, 233, 217, 187 and 161.

PMR: O ^ q ₁ 0.8 (m, terminal methyls), 1.28 (s, according to dimethyl), 2.67 (m, bensylmethine), 3.70 (m, carbinolmethine), 6.69 (i.e. , J = 2 Hz, ArH), 6.82 (dd, J = 8 and 2 Hz, ArH) and 7.07 (d, J = 8 Hz, ArH).

Trans ~ 4-pentyl -cis-3 "L4-- (1,1-dimethylhep- tyl) -% 2-hydroxyphenyl -3 - cyclohexanol ( 225mg , 76%) of cis-3- £ 2-benzyloxy-4- ( 1,1-dimethylheptyl) phenyl 3-trans-4- (2-pentenyl) cyclohexanol (363mg, 0.762mmol)

Melting point: 135 to I36 ⁰ C.

PMR iii Q ^ ₁ 0.8 (m, terminal methyls), 1.23 (s, gem. Dimethyl), ³ 2.65 (m, Benzylmethin), 3.75 (m, Carbinolmethin), 4.88 (s , OH), 6.78 (m, ArH) and 7.02 (d, J = 8 Hz, ArH).

CJG-3 'L4 (1> 1-3), imethylpentyi) _i »2-hydroxyph enyl] - CYCLOHEPTA e3: anol (2.5 g, 60%) of cis-3-E2-benzyloxy-4- ( 1,1-dimethylpentyl) phe

nyl-cyclohexanol (5.5 g »0.0144 mol) ₀

Melting point: 112 to 113 ^° C (from pentane, isopropyl ether) ♦

IR: (CHCl ₃ ) 3636, 3390, 1631 and 1592 cm ^-1 .

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

PMR: 6 ¹ ^ ₁ 0.80 (m, tenninal methyl), 1.20 (ε, according to dimethyl), 2.90 ^ (m, benzylmethylene), '3 »61 (m, carbinol methine) and 6.4 - 7.1 (m, ArH).

Analysis: Calculated for C ₁₉ H ₃₀ O ₃ JC, 78.57j H, 10.41 %. Found: C, 78.76} H, 10.11 %.

Trans-3-f 4- (1,1-dimethylpentyl) -2-hydroxyphenylcyclohexanol (385mg, 78 %) of trans-3-C2- (Bensyloxy-4- (1-1-dimethylpentyl) -phenyl) cyclohexanol ( 64Ο mg, 1.68 mmol).

Melting point: 114-115 ⁰ C (from pentane) * IR: (CHCl ₃₎ 3636, 3390, 1631 and 1577 cm ^"1 MSi m / e 290 (M ^+), 272, 233 and 215..

PMR: O ^ H ₁ 0.80 (ία, terminal methyl), 1.27 (s, according to dimethyl), ^ 3.30 (m, benzylmethine), 4.28 (m, carbinolmethine), 4.72 ( bs, OH), 6.81 (dd, J = 8 and 2 Hz, ArH), 6.81 (d, J = 2 Hz, ArH) and 7.03 (d, J = 8 Hz, ArH).

Analysis: Calculated for C ₁ QH ₃₀ O ₂ : C, 78.57; H, 10.41 %. Found: C, 78.38; H, 10.10 %

cis-3-C4- (1: 1 1-Dirnethylhexyl) -2-hydroxy phenylJcyclohexanol (2.3 g, 99%) of cis-3-L2-3enzyloxy-4- (1,1-dimethylhexyl) phenyljcyclo-

hexanol (3.00 g, 7.61 mmol).

Melting point: 98 to 100 ⁰ C (pentane) IR: _(CHCl3) 3636, 3367, 1626 and 1587 cm "^'1.

MS: m / e 304 (M ⁺ ), 286, 233 and 215 ·

PMR: tm 0.82 (m, tenninal methyl), 1.20 (s, according to dime-

ethyl), 2.92 (m, benzylmethine), 3.76 (m, carbinolmethine) and 6.65-7.4 (m, ArH).

Analysis: Calculated for C ₂₀ H ₃₂ O ₂ : ^c »78.895 H, 10.59 % · Found: C, 78.57? H, 10.46 %.

Trans-3 "C4 -" (1 > 1-D- imethylhexyl) -2-hydroxy and phenylcyclohexanol (440 mg, 86 %) of trans-3-benzyloxy-4- (1,1-dimethylhexyl) phenyl-1-cyclohexanol (660mg, 1.68mmol).

Melting point: 113 to 114 ^° C. (pentane)

IR: (CHCl ₃ ) 3636, 3390, 1631, 1616 and 1580 cm ^-1 .

MS: m / e 304 (IiI ⁺ ), 286, 233 and 215. HRMS: 304.2419 (C ₂₀ H ₃₂ O ₂ )

cis-3- [4- (1,1 " -dimethylnonyl) -2-hydroxy- oxyphenyl3-cyclohexanol (4.0 g, 100 %) of cis -3- 2-benzyloxy-4- (1,1- ! dimethylnonyl) phe nyl] cyclohexanol (5, Og, 1.15 mmol). melting point: 82-83 ⁰ C (pentane) IR:. (CHCl ₃₎ 3650, 3390, 1637 and 1597 cm "" ¹ MS: m / e 346 (M ⁺ ), 328, 233 and 215.

Analysis: Calculated for C ₂₃ H ₃₈ O _2: C, 79.71; H, 11.05%. Found: C, 79.71; H, 11.14%.

trans-3- Γ4- (1 ₈ 1 -Dirne thylnonyl) -2-hydroxyphenyl l * f cyclo hexanol (709 mg, 89%) of trans-3-L2-benzyloxy-4- (1,1-dimethylnonyl) phenyl} cyclohexanol (1.00 g, 2.29 mmol). Melting point: 69 to 70 ^° C. (pentane). IR: (CHCl ₃ ) 3636, 3413, 1631, 1618 and 1582 cm ^-1 . MS: m / e 346 (M ⁺ ), 328, 233 and 215.

PBIR: cT ™ _ 0.87 (m, tenninal methyl), 1.22 (s, according to dimethyl), 3.30- ⁱ (m, benzylmethine), 4.22 (m, carbinol methine), 4.98 (bs, OH) and 6.7-7.3 (m, ArH).

Analysis: Calculated for ^C ₂ ^H 3 38 ° 2 ^{: C>} 79 »71; H, 11.05 %. Found: C, 79.11; H, 10 ₉ 86 %.

cis-3- / 4-- (1,1-dimethyldecyl) -2-hydroxyphenyl-7'-cyclohexaol (2.02 g, 98 %) of cis-3/2-benzyloxy-4 - (i, 1 - dime thyldecyl.) /. cyclohexanol (2.6 g, 5.78 mmol)

 Melting point: 93 "to 94 ° C (pentane)

IR: (CHCl ₃ ), 3636, 3390, 1629 and 1587 cm ^-1 . MS: m / e 36Ο (M ⁺ ), 342, 288, 233 and 215.

PMR: d QjJq 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 C ₂₄ H ₄₀ O ₂ : C, 79.94; H, 11.18 %. Found: C, 80-, 12; H, 11.39 %.

Trans -3 ~ / 4- (1,1-dimethyldecyl) -4- hydroxyphenyl / cyclohexanol (130 mg, 45 %) of trans-3/2-benzyloxy-4- (1,1-dimethyldecyl) -phenyl / cyclohexanol (36Ο mg, 0.80 mmol). Melting point: 76 to 77 ^° C.

IR: (CHCl ₃ ) 3636, 3425, 1631, 1616 and 1580 cm ^-1 . MS: m / e 36Ο (M ⁺ ), 342, 233 and 215.

PMR: σ QJ) Q ₁ 0.86 (m, terminal methyl), 1.22 (s, according to dimethyl), 3.2 (m, bensylmethine), 4.17 (m, carbinol methine and OH) and 6, 6 - 7.2 (m, ArH).

Analysis: Calculated for ^C 24 ^H 40 ° 2 ^{: C>} ^ ⁹ , 94; H, 11.18 %. Found: C, 80.20; H, 11.27 %.

cis-3- / 4- (i, 1-dimethylundecyl) -2-hydroxyphenyl7cyclohexanol (2.39 g, 85%) of cis-3-Z2 "" ^Ben y ^lox 5 ^r -4- (1, 1 -dimethylundecyl) · -Phenyl / cyclohexanol (3.5 g, 7.54 ml viol).

Melting point: 85 to 86 ^° C.

IR: (CHCl ₃ ) 3636, 3390, 1634 and 1592 cm ^-1 . MS: m / e 374 (M ⁺ ), 356, 233 and 215.

PMR: d ^ y 0.89 (m, terminal methyl), 1.22 (s, according to dimethyl), 2.98 (m, benzylmethine), 3.95 (m, carbinolmethine), 6.83 (m, ArH) and 7.09 (d, J = 8 Hz, ArH).

- 70 - 207 7

Analysis: Calculated for ^C 25 ^H 42 ° 2 ^{i C} » ⁸⁰ » ¹ 5 » ^H » ¹¹ f3 ° % · Found: C, 80.00; H, 11.48 %,

trans-3- r4- (1,1-dimetyliyl-2-yl) -2-hydroxyphenyl] cyclohexanol ( 487m, 60 %) of trans-3-l-2-benzyloxy-4- (1,1-dimethyl-2- ol)

cyl) phenyl3cyclohexanol (1.00 g, 2.16 mmol) · Melting point: 73-74 ⁰ C.

IR: (CHCl ₃₎ 3636, 3413, 1637 and 1585 cm-, "^'1.

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

PMRt ^^ x 0.89 (m, terminal methyl), 1.27 (s, according to dimetyl), 3.25 (in, benzylmethine), 4.31 cm, carbinolmethine), 5.07 cbs, OH ) and 6.7 ..- 7.3 (m, ArH).

Analysis: Calculated for CH ₄₂ O ₃ : C, 80.15; H, 11.30 %, Found: C, 80.11; H, 11.16 ^.

cis-3-l-4- ( 1' -dimethylheptyl) -2-hydroxyphenyllcyclooctanol CO, 793 g, 73 %) of cis-3-t2-benzylo2: y-4 ~ (1,1-dimethylheptyl) phe ·

nylcyclooctanol (1, 36 g, 3.11 mmol).

Melting point: 89 to 90 ^° C. (from pentane).

MS: m / e 346 (M ⁺ ), 328, 261 and 243.

PMR: V ¹ ^ Qi 0.83 (m, terminal methyl), 1.22 (s, according to dimethyl), 3.0 3 (bm, benzylmethine), 3.98 (bm, carbinolmethine), 6.75 ( m, ArH) and 7.00 (d, J = 8 Hz, ArH).

Analysis: Calculated for ^C ₂ 3 ^H 38 ° 2 ^: ° * ^ ⁹ » ⁷¹ » ^H » ¹¹ » ° 5 % · Found: C, 79.90; H, 10.89 %.

trada-3-C4- (1,1-dimethylheptyl) -2-hydroxyphenyl-7-cycloocotungole (2.62 g, 83 %) of .tranan-3- [2-bensyloxy-4- (1,1-dimethylheptyl) phenyllcyclooctanol (4.0 g, 9 _S 17 mtiol)

Melting point: 76 to 77 ^° C (from pentane). MS: m / e 346 (3Si ⁺ ), 328, 261 and 243 ·

PMR: O ^mS 0.83 (m, terminal methyl), 1.24 Cs, acc. Whore CDGl ^

207 79

thyl), 3.15 ("hm, benzylmethine), 4.05 (m, carbinolmethine), 6.78 (m, ArH), and 7.02 (d, J = 8Hz, ArH).

Analysis: Calculated for C ₂₃ H ₃₃ O _2: C, 79.71; H, 11.05 %. Found: C, 79.81; H, 10.86 %.

Example 5:

$ - $ - 2nd -Benzyl Oxi-4-- (1,1-d ime t hylheptyl) phenyl ^ cycl A solution of 3.89 g (10 mmol) ohez-2-enone 2- (3-benzyloxy-4-bromophenyl) -2- Methyloctane in 10 ml of tetrahydrofuran was added slowly to 360 mg (14.4 mmol) of magnesium metal with a sieve fineness of 70 to 80 mesh. The resulting mixture was boiled for 30 minutes under reflux and then cooled to 0 ⁰ C. To this solution was slowly added a solution of 1.40 g (10 mmol) of 3-ethoxy-2-cyclohexene-1-one in 3 ml of tetrahydrofuran. The Reak? tion mixture was stirred for 30 minutes at 0 ⁰ C and then quenched by the addition of 20 ml of 1N sulfuric acid and heating on a steam bath over a period of 30 minutes. »It was then cooled and added to 200 ml of ether / 200 ml of water. The organic extract was washed successively with 200 ml of saturated sodium bicarbonate and 200 ml of saturated sodium chloride, dried over magnesium sulfate and evaporated to an oil. The crude product was purified by column chromatography on 170 g Sicicagei eluting with a 1: 1 mixture of ether and pentane to give 2.5 g (54 %) of the partial compound as an oil.

PMR: Qjβl ° ' ⁸ ^ ^ ⁵ terminal side-chain methyl ), 1.30 (s, according to dimethyl), 2.05 (dt, J = 6 & 6 Hz, C-5-ethylene), 2.50 (t, J = 6Hz, C-4-methylene), 2.80 (t, J = 6Hz, C-6-methylene), 5.19 (s, benzylethermethylene), 6.30 (t, J = 1Hz, Vinyl proton), 7.00 (dd, J = 8 and 2 Hz ₅ ArH), 7.02 (d, J = 2 Hz ₅ ArH), 7.25 (d, J = S Hz, ArH) and 7.45 (s, PhH)

IR: (CHGl ₃₎ 1667, 1610 and 1558 cm ^"1

MS: m / e 404 (M ⁺ ), 319, 313 and 91.

Similarly, 3-E2-benzyl- loxy-4- (1,1-aminoethyl-phenyl) -phenyl ] -4-methylcyclohexyl -2-enone was used as an oil (4.12 g, 77%) of 3-Athoyl-6-methyl-2-cycloheis: en-1 "on (1.98 g, 12.9 mmol), magnesium (0.61 g, 25.7 mmol) and 12.9 mmol (5, 0 g) of 2- (3-benzyloxy-4-bromophenyl) -2-methyloctane. IR: (CHCl ₃ ): 1667, 1613 and 1565 cm ^-1 . MS: m / e 418 (M ⁺ ), 400, 385 _s 333, 327, 299, 291 and 91.

PMR: ^ g ₁ 0.85 (m, terminal methyl), 1.02 (d, J = 7 Hz, methyl), ³ 2.45 (m, methylene) ,. 3.2 (m, Alkylinethin), 5 , 10 (s, benzylmethine), 6.01 (d, J = 1 Hz, vinyl H), 6.90 (m, ArH), and 7.37 (s, Ph).

The following compounds are similarly prepared from appropriate 3-alkoxy-2-cycloalkene-1-ones and 2-bromo-5- (Z-W-substituted) phenylbenzyl ethers:

H OCH (CHO) (CH ₀ ). C ^ H ₁

6 ⁿ 5

H OCH ₂ C ₆ H ₅

H 0 (CHg) ₈ ^C 6 ^H 5

H 0 (CHg) ₄ 4-PC ₆ H ₄

H ^{O (CH} 2> 10 4 -ClC ₆ H ₅

H 0 (CHg) ₁₃ C ₆ H ₅

H 0 (CHg) ₁₃ H

H OC (CH ₃₎ g (CHg) ₅ H

HO C ₆ H ₅

H CH _(CH3) (CHg) ₃ C ₆ H ₅

2'4 ο 5

tr t ft \ TT

ü ν0Η _ο ) _η Η

207 79

R ₂ Z (CH ₂ ) ₃ Example 6: W H (CH ₂ ) ^ ₀ 2-pyridyl H CH (C ₂ H ₅ ) (CH ₂ ) ₂ 4-pyridyl H CH (CPI ₃ ) CH (CH ₃ ) CH ₂ 4-pyridyl H O (CH ₂ ) ₂ 3-pyridyl H O (CH _{2) 1O} 4-pyridyl H (CH ₂ ) 0 (CH ₂ ) ₃ 2-pyridyl H (CH ₂ ) ₂ O (CH ₂ ) ₁₀ H H - (CH 2) ₄ OCH ₂ H H (CH ₂ ) ^ OCH ₂ hh H CH (CH ₃ ) CH (CH ₃ ) (CHO) ₅ 4-ClC ₆ H H C (CH) (CH) _ H H * ^ά 2 * H

3-L2-benzyloxy-4- (1,1- dimethylhephenyl ) phenyl-β-me- thyyloylojanepanone.

To a temperature of -10 ⁰ C to -5 ⁰ C having solution of 4 »17 mmol Dimethylkupferlithium in 10 ml of tetrahydrofuran were slow. 5 »60 ig (1.39 mmol) of 3-L2-benzyloxy-4- (1» 1-dimethylheptyDphenyl] cycloxy-2-enone in 5 ml of tetrahydrofuran were added. The reaction mixture was stirred for 30 minutes and then 100 ml of saturated ammonium chloride After stirring for 10 minutes, the quenched reaction mixture was extracted with 200 ml of ether The ether extract was washed with 100 ml of saturated sodium chloride, dried over magnesium sulfate and evaporated to an oil. The oil was reduced to three by preparative thin layer chromatography Purified 20 cm χ 20 cm χ 2 mm silica gel plates with a 2: 1 mixture of cyclohexane and ether to give 282 mg (48 %) (higher Rf) of the title compound as an oil and 211 mg (36 %) ( lower Rf) 3 - (2-Benzyloxy-4- (1-1-dimethylheptyl) phenyl-1-methylcyclohex-2-en-1-ol in the form of an oil.

_Q? I telnet un%:

PMR: ^ "ο ^] _ * 0.82 (m, partial side-chain methyl), 1.22 (s,

gem. Dimethyl), 1.40 (s, C-3-methyl), 2.30 and 3.05 (AB quartet, -Jβ-14Hz, C-2-methylene), 5.02 (s, benzylethermethylene), 6,6 -

7.3 (m, ArH) and 7.25 (s, .PhH). IR: (CHGl ₃₎ 1704, 1610, 1565 cm * ^'1.

MS: m / e 420 (M ⁺ ), 405, 377, 335 and 329.

3- ( 2-Benzyloxy -4- (1,1-di - methylheptyl) phenyl ] -I ^ 2-en-1-ol:

PMR: cf.TM. 0.82 (m, terminal side-chain methyl), 1.25 (s, according to dimethyl), 1.30 (s, C-1-methyl), 2.34 (in, C-4-methylene ), 5.00 (s, benzylethermethylene), 5.65 ("bt, J = 1Hz, vinyl proton), 6.7-6.9 (m, ArH), 7.00 (d, J = 8Hz, ArH) and 7.30 (a, PhH). IR: (CH 2 Cl 2) 3571, 340I, 1661, 1608 and 1585 cm ^-1 . MS: m / e 420 (M ⁺ ), 402, 335 and 317.

Repeating this procedure, but using the appropriate cyclohex-2-enones of Example 5, compounds having the following formula wherein Z and V / are as defined in Example 5 are recovered.

Example 7;

A mixture of 400 mg (0.988 mmol) 3 - / <2-benzyloxy-4 ~ (1,1-dimethylheptyl) phenyl 7cyclohsx-2-Gnon and 20 mg 5 % Palladiuia on charcoal was placed under a hydrogen pressure for 30 minutes stirred by an atmosphere. The reaction mixture was filtered through ethereal diatomaceous earth and the filtrate was evaporated to a solid. The crude solid was precipitated. Petreläther recrystallized to give 110 mg C35 / S) of the title compound j melting point 122-123 ⁰ C.

PMR: <f-1, *, 0.82 (m, terminal side-chain methyl), 1.30 (see.

Dimethyl, 2.19 (dt, J = 6 and 6 Hz, C-5-methylene), 2.52 (z, J = 6 Hz, C-4-methylene, 2.80 (t, J = 6 Hz, C-6-methyl), 6.7-7.4 (m, ArII and

Vinyl praton) and 8, 16 (s, phenol), IR: (KBr) 3448, 1634, 1634, 16OÖ. and 1565 cm "* ¹ KS: m / c 314 (M ⁺ ), 299 and 299.

Analysis: Calculated for C _g H ₃₀ O ₃ : C, 80.21, H, 9.62 %, Found: C, 80.23; H, 9.46%.

In the same way, the remaining 3- / 2-benzyloxy-4- (ZW) phenyl __ / e ^ cloalk-2-enones of Example 5 are converted to the corresponding 3- / 4 "- (Z-) ~ 2-hydroxyphenyl _p _7cycloalk-2-enone converted.

Example B:

A mixture of 6.8 g (19.3 mmol) of 3/2-hydroxy-4- (4-phenylbutyloxy) phenyl-1-cyclohexanone ethyl ketal, 100 ml of 2N hydrochloric acid and 60 ml of dioxane was refluxed for one hour. The reaction mixture was cooled and added to 300 ml of ether / 500 ml of saturated sodium chloride. The ethereal extract was sown once with 500 ml.

washed with saturated sodium bicarbonate, dried over magnesium sulfate and evaporated to an oil. The oil was purified by column chromatography on 400 g of silica gel eluting with a 1: 1 mixture of ether and cyclohexane to give 6.4 g (98 %) of the title compound as an oil,.

PMR: <f ™ _λ 2,69 (m, benzyl-ethylene), 3,90 (bt, J = 6 Hz, -

6.25-6.5 (in, ARH), 6.82 (d, J = 8 Hz, ArH) and?, 20 (s _s PhH). IR: (CHCl ₃ ) 3571, 3333, 1718 (weak), 1626 and 1595 cm ** ¹ . MS: m / e 388 (M ⁺ ), 320, 310, 295, 268 and 91.

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

3 ~ 4 ^ - (2-Hepty_loxy) ~ 2-hydroxyphenyj ^ 7cyclohexanone (4.7 g, .82%), in

Form an oil of 6.0 g (18.8 mmol) of the corresponding methyl ketal, IR: (CHCl ₃ ) 3636, 3390, 1724 (weak), 1639 and 1600 cm ^-1 , HS: m / e 304 (M ⁺ ). , 206, 188, 171, 163 and 137.

PMR: cf ^ ₁ 0.82 (ra, methyl), 1.25 (d, J = 6 Hz, methyl), 4.15 (a, 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

Form an oil of 5.0 g, (15.0 mmol) of the corresponding methyl ketal, IR: (CHCl ₃ ) 3636, 3378, 1721 (weak), 1631 and 1595 cm ^-1 . MS: m / e 318 (M. ⁺ -), 206, I88, 178 and 1b1.

r TMS PMR: δ CJ) C ₁ 0.84 (m, methyl), 4.20 (m, side chain methine), 6.39

(dd, J = 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 ε. IR: (CHCl ₃ ) 3584, 3367, 1709 (weak), 1626 and 1587 cm "* ¹ MS: ffi / e 332 (M ⁺ ), 206, 18" and 171.

PMR: <f ™. 0.85 (m, methyl), 4.26 (m, side chain methine), 6.39

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

(3yg,

79 %) from 5.0 g (14.2 mmol) of the corresponding methyl ketal in the form

an oil. '

IR: (CKCl) 3636, ^ 3O, 1724 (weak), 1637 and 16ΟΟ cm "* ¹ .

MS: M / e 338 (M ⁺ ), 206, 188, 132, 117 and 91.

PMR: (iJj ^ 1.19 and 1.27 (d, J = 6Hz, methyl), 3.02 (in, 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).

(^ »4 * 5 g, 89 fo)

in the form of an oil of 5.2 g (13.6 ml) of the corresponding methyl ketal. IR: (CHCl) 3636, 339Ο, 1718, 1637 and 16ΟΟ cm ^-1 . MS: m / e 366 (M ⁺ ), 206, 188 and 91.

PMR: <f ^ ₁ 1.25 (d, J = 6 Hz, methyl), 3.07 (m, methine), 4.19 (m, methine), 6.32 (dd, J = 9 and 2 Hz , ArH), 6.32 (d, J = 2 Hz, ArH), 6.78 (d, J = 9 Hz, ArH) and?, 14 (s, Ph) "

Example 9 ;

cis-3/2-Hyjirox2-4- (4-phenylbutyloxyphenyIl7cyclohexanol and the trans isomer

To a solution of ~18 ⁰ C from 4.8 g (14.2 in mol) of 3- / 2-hydroxy-4- (4-phenylbutyloxy) phenyl-7-cyclohexanone in 25 ml of methanol was added 0.539 lb Ci4, 2 mmol) sodium borohydride. The reaction mixture was stirred for 40 minutes, then added to 250 mL of saturated sodium chloride / 250 mL of ether. The ether extract was once with 150 ml]

Washed with saturated sodium chloride, dried over magnesium sulphate and evaporated to an oil, the oil was purified by means of the column chromatography

tography on 400 g of silica gel eluting with a 2.5: 1 mixture

purified from dichloromethane to give 3.37 g (70%) of the cis-isomer, crystallized from cyclohexane, and 0.68 g (14 %) of the trans isomer, crystallized from cyclohexane, and 0.69 g (• 14 %) mixed material. -

cis-isomer

Melting point: 79 to 80 ^° C.

PMR: cf J ₀ J ₁ 2.70 (m, benzylmethylene), 3.26 (ra, benzylmethine), 3.93 (bt, J = 6 Hz, -OCH ₂ -), 4.28 (yes, OH, Carbinolmethine, with D ₃ O 4,25, M, carbinolraethine), 6,42 (dd, J = 8 and 2 Hz, ArH), 6,45 (d, J = 2 Hz,

ArH), 7.03 Cd, J = 8 Hz, ArII) and 7.22 (s, PhH).

IR: (CHCl) 3610, 3333, 1631 and 16Ο3 in the " ¹ .

MS: m / e 340 (M ⁺ ), 322, 190 and 91..

Analysis: Calculated for C ₂₂ H ₂ g0: C, 77.61; H, 8.29%.

Found: C, 77.46; H, 8.25%.

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

PMR: O ^r J ₁ Jg ₁ 2.68 (m, benzylmethylene), 3.3 O (ta, OH,. OcHg,. Carbolin methine, with DpO 3.63, m, carbolinemethine and 3.90, bt, J = 6 Ha, -OCH 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, PhH), IR: (CHCl) 3610, 3390, 1631 and 1595 cm ^-1 .

MS: m / e 340 (M *), 322, 190 and 91..

Analysis: ^C ₂₂ ^H 28 Berechnet'für ° ^{3: Cf} 77.61; H, 8.29%.

Found: C, 77.40; H, 8.31%.

In the same manner, the following compounds were prepared; _t / 4 »(2- ^ eptyloxy) -2-hydroxyphenylcyclohexanol

and the transisomer in the form of oils of 3- / 4- (2 "heptyloxy) -2-hydroxyphenyl / cyclohexanone (5" 2 g, 13.6 mmol). In order of elution of silica gel, 854 mg (36 %) of the cis-3 and 107 mg (3 %) of the trans-3 isomer were added.

IR: (CHCl ₃₎ 3597, 3333, 1629 and 16ΟΟ cm ^"1 • *. MS: m / e 306 (M ^+), 208, 190, 173 and 1œ2.

PMR: if ^ ₁ 0.82 (ta, methyl), 2.8 (κ, benzylmethine), 3.7 (m, carbene)

binolmethine and OH), 4.1 (m, methine), 6.38 (m, ArII) and 6.93 (d, J = 8 Hz, ArH)

 trans:

PMR: (Γ ι ¹ " ¹ ?, 0.82 (m, methyl), 3.25 (ffl, benzylmethine), 4.3 (m, car-

MS: m / e 306 (M ⁺ ), 208 and 190.

TMS CDCl

binolmethine and OH), 6.33 («a, ArH.) and 6.94 (d, J = 8 Hz, ArH).

cis -3- / 4- (2-octyloxy) -2-hydroxyphenyl-cyclohexanol and the transisomer of 3- (4-nonyloxy) -2-hydroxyphenvl-7cyclohexanone (3.15 g,

19.48 mmol). In order of elution with silica gel, 2.11 g, (67 %) of the cis-3- and 0.32 g (1Q.q of the trans-3 isomer were recovered as oils.

ice: .

IR: (CHCl ₃ ) 3663, 3390, 1639 and 1610 cm ^-1 . MS: m / e 334 (M ⁺ ), 316, 208 and 19Ο.

PMR: / ^ ₁ -0.88 (m, methyl), 2.85 (m, benzylmethine), 3.5-4.1 (m, carbinolmethine and OH), 4.22 (m, side-chain mthhin), 6, 38 (m,

ArH) and 6.97 (d, J = Hz, ArH).

tr ans :

IR: (CHCl ₃ ) 3636, 3413, 1637 and 1592 cm ^-1 .

MS: m / e 334 (M ⁺ ), 316, 208, 206 and 19Ο.

PMR: (f ^ iS ₁ 0.88 (m, methyl), 3.23 (m, benzylmethine), 3.9-4.6 (m,

Carbinol and side chain tenethine and OH), 6.36 (m, ArH) and 6.96 (d, J s 8Hz, ArH).

cis - 3 - (2-4-phenoxy) butyloxy) -2-hydroxyphenyl- _J / cyclohexanol; and the trans isomer of 3 - / 4- (2- (4-phenyl) butyloxy) -2 ~ hydroxyphenycyclohexanone (2.9 g, 8, "23 mmol). In order of elution with silica gel, the 1.29 g (44 %) of the cis-3 ~ and 241 mg (8 %) of the trans-3 isomer won

ice:

Melting point: 96 to 105 C (from pentane) IR: (CH 2 Cl 2) 3636, 3390, 1634 and 1608 cm ^-1 . MS: m / e 340 (M ⁺ ), 322, 208, 19Ο, 162 _S 147, 136 and 91 ,

_ φΜς

PMR: ό QSQ ₁ 1.30 (d, J = 6 Hz, methyl), 3.75 (m, carbinol methine), 4.23 (m, side chain rivine), 6.21 (d, J = 2 Hs, ArH) , 6.38 (dd, J - 8 and 2 Hz, ArH), 6.98 (d, J = 8 Hz, ArH) and 7.20 (s, ph).

Analysis: Calculated for C ^ K ^ O: C, 77.61; H ₁ 8.29%.

Found: C, 77.59; K, 8,18%.

trans:.

IR: (CHCl) 3623, 3390, 1037 and 1595 cm * " ¹ , MSi m / e 340 (M ⁺ ), 342, 208, 190, 162, 147, 13δ and 91.

PMR: <f cDci ^{1 '30} Cd, J s 6 Hz, methyl), 3,3 (m, ezyl-araethine), 4,23 (m, carbinof and side chain methine), 6,38 (m, ArII), 6, , 94 (d, J = 8 Hz, ArH) and 7.18 (s, Ph).

cis-33/4 "(2- (6-Phengl) hex ^ loxy) _{-2-hydroxyphenyj;} 7 ^f cyclohexanone and the trans isomers of 3 ~ 4- (2- (6-phenyl) hexyloxy) -2-hydroxyphenyl cyclohexanol (3.3g> 9 »01 mmol) In the series of silica gel elution, 1.54g (46 %) of the cis-3 'and 274mg (8%) of the trans iso-ine were recovered.

ice:.

Melting point: 99 to ⁰ II3 C (from pentane). IR: ^ CHCl) 3636, 3367, 1631, and 1592 era ¹ MS: ra / e 368 (M ⁺ ), 350, 208, 190, 162, 147, 136, and 91.

PMR: iT CPc ₁ 1.30 (d, J = 6 Hz, methylene), 3.6 (m, Carbinolmethin), 4.2

(κ, side chain methine), 6.3? (ra, ArH), 6.98 (d, J = 8 Hz, ArH) and

7.18 (s, PhH).

Analysis: Calculated for C ₂₄ H ^ O: C, 78.22; H, 8.75%.

found: C, 78.05; H, 8.56 "%.

trans:

IR: (CH 2 Cl 2) 3636, 3413, 1634 and 1597 cm ^-1 .

ESi m / e 368 (M ⁺ ), 350, 208, 190, 162, 147, 136 and 91.

PMR: cT ^ ₁ 1.25 (d, J = 6 Hz, methyl), 4.21 (ra, carbinol and silane)

3 chain methine) _$ 6.37 (m, ArH), 6.95 (d, J = 8 Hz, ArH) and 7.15

Cs, PhH).

Example 10:

The procedure of Example 1 is repeated, however

7

the appropriate 2 ~ Broa-5- (Z-W-substituted) phenolbenzyläther and 2-cycloalkene-1-ones used as reactants. The following compounds are obtained:

0 H 2 H 3 H O H 1 H 1 H. O H 2 H Λ H 3 H 1 H - O H 3 H 1 H 1 H 1 1 1 CH ₃ n-C_H " Λ 1 CH ₂ C ₆ Il ₅ 0 C ₂ H ₅ ^f

OCH (CH g ₃

OCH (CH ₃ ) (CH ₂ ) ₃ OCH (CH ₃ ) (CH ₂ )

OCH (CH ₃ ) (CH ₂ ) g ₂

₃ OCH (CH ₃ ) CH

₃ OCH ₂ CH (CH

OCH (CH ₃₎ (CH _{2) 3} OCH (CH ₃₎ (CHg) ₃

OCH (CH ₃₎ (CH _{2) 3} OCH (CH ₃₎ (CH _{2) 3} OCH (CH ₃₎ (CH _{2) 3} OCH (CH.

C ₆ H ₅ C ₆ H ₅

C ₆ H ₅

C ₆ H ₅

C ₅ H ₅ C ₆ H ₅ C ₆ H ₅

a x ^ 2_

2 2 3 3 3 O O 1 1 1 1 2 2 2 2 3 3 3 O 2 O O O 1 1 2

CH

CH

CH ₃

nc ₃ H _?

CgH ₅

CH ₃

iC ₃ H _?

CH ₂ C ₆ H ₅

(CH ₃ ) ₃ C ₆ H ₁

C ₂ H ₅

(CHg) ₃ X ₆ H ₅

CH ₃

CH ₃

CH

CH ₂ CgH ₅

iC ₃ H _?

CH, OC (CH ₃ ) ^ (CHg) ₁₀

OCH (CgH ₅ ) (CH ₂ ).

0 (CHg) ₃ C (CH _3] 0 (CHG) ₆

C (CH) ₂ (CHg) ₆

(CHg) ₅ (CHg) ₅

CHg (CH ₀ )

g) ₈

HS HS

H H

HS

H H H H H H H H H H H H H H H H H H II

HS

~ 84 -

O Λ Λ 1 1 1 3 1 1 1 23 ο3 O O1 * ι

1 1 2 3 O 1 2

1 1 1

H H

H.

H H H H H H

(CH ₂ ) ₅ ; hh CH _(CH3) (CHg) ₃ hh CH _(CH3) (CHg) ₃ hh CH _(CH3) (CHg) ₃ hh CH _(CH3) (CHg) ₃ hh GH (CH ₃₎ (CHg) ₂ hh CH (CH ₃ ) (CKg) ₂ hh CH (CH ₃ ) CH (CH ₃ ) (CH ₂ ) - H CH (CH ₃ ) (CHg) ₂ ^C 6 ^H 5 CH _(CH3) (CHg) ₃ 4-FC ₆ H ₄ CH (CgH ₅ ) (CHg) ₂ 4-ClC ₆ H ₄ cH (c ₂ H ₅ ) (cH ₂ ) ₄ 4-FC ₆ H ₄ C (CH J ₂ (CH) H 1 * 1 V / U ~ ) r-> ^ V / iio Jn J d CC- H H C (CH) ₂ (CHg) ₁₀ H hh ν I Uu λ jf ~ \ ν ν Χ * λ j / * \ H C (CH ₂ J (CHg) ₁₀ H C (CH) ₂ (CHg) ₁₀ H. C (CH ₂ J (CHg) ₁₀ H H (CHg) 0 (CHg) H (CHg) ₃ O (CHg) ₃ H (CHg) ₃ O (CHg) ₅ H (CHg) ₂ O (CHg) ₈ H (CHg) ₆ O (CHg) ₇ H (CH ₃ ) ₃ O (CH ₃ ) ₃ H CH ₂ O (CH ₂ ) _? H (CHg) ₂ O (CHg) H (CH ₂ ) 0 (CHg) ₂ H

1 H (CHg) ₂ O (CHg) ₁₀ H 1 H- C (CH) g (CIIg) ₂ O (CIIg) _z H 3 H (CHg) ₁₀ O (CHg) ₂ H 2 CH ₃ (CH 2) ₄ OCH ₂ HS O CH ₃ (CH 2) ₆ O HS 1 CH ₃ (CH 2) ₆ O HS 3 CH ₃ (CH 2) ₆ O HS O CH ₃ (CH 2) ₆ O H Λ CH ₃ (CH 2) ₆ O H CVI ^CH -C ³ H (CH 2) ₆ O HS 1 (CH 2) ₆ O HS 1 CHGC ₆ H ₅ (CHg) ₁₃ O H 1 (CH 2) ₄ C ₆ H ₅ ^(CH 2 ⁾ 13 ° H 1 H (CH 2) ₆ O HS 1 H (CHg) ₁₃ O HS 1 H (CH 2) ₆ O 4-Fc ₆ H ₄ 1 C ₂ H ₅ (CH 2) ₆ O 4-FC ₆ H ₄ 3 CH ₃ (CH 2) ₆ O 4-ClC ₆ H ₄ O CH ₃ (CHg) ₁₃ O 4-FC ₆ H ₄ 1 CH ₃ CH (CH ₃ ) (CH ₂ ) ₂ O HS 1 CH (CH ₃ ) (CH ₂ ) ₂ O HS 1 ν \ jil r \ J O ίΓC fc (^ Q ~ y CH (CH ₃ ) (CH ₂ ) 0 HS O C ₂ H ₅ "CH (CH) (CHg) ₆ O H 1 ^CH 3 - (CH ₂ ) ₂ CH (CH ₂ O ₂ CH ₂ H 1 CH, CHgC (CH OgCH ₂ H 1 CU. Γ * f t * XX \ f FVi \ HS 1 H CH _(CH3) (CHg) ₃ 4-pyridyl O H CH _(CH3) (CHg) ₃ 4-pyridyl 3 H- CH _(CH3) (CHg) ₃ 4-pyridyl Λ CH ₃ (CHg) ₃ 2-pyridyl 3 CH (CHg) ₃ 2-pyridyl

sg

O 2 5 H H 1 H CH ₃ 1 CH ₃ H O nC ₄ H t ~ C ₄ H ₉ 2 cL O ρ H 1 CH ₂ C ₆ H ₅ H 3 ^ 3 ^H 7 1 C ₂ H ₅ ³ 3 ^C 2 ^H t> 1 O H 2 CH 2 1 H 1 1 H O O CH ₃ 2 H 3 ^CH 3. H O H 1 CH ₃ H 3 ^C 2 ^H 5. 1 2 VJJ O O 1 3 2

CH (CH ₃ ) CH (CH) CH ₂

CH (CH) CH (CH) CHg

CH (CgH ₅ ) (CHg) ₂

CH (C ₂ H ₅ ) (CHg) ₂

CH (C ₂ H ₅ ) (CHg) ₂

CH (C ₂ K ₅ ) (CH ₂ ),

CH _(CH3) (CHg) ₃

₃ )

(CH ₂ ) ₃ 0

(CHg) ₃ 0

(CH ₃ ) ₃ O

(CH ₃ ) ₃ OCH (CH ₃ )

(CH ₃ ) ₃ OCH (CH ₃ )

(CH ₃ ) ₃ OCH (CH ₃ )

CH _(CH3) (CHg) ₂ 0 (CH _{2) 4}

CH _(CH3) (CHg) ₂ O (CHG) ₄

CH (CH ₃ ) (CH ₂ ) ₂ O (CH ₂ ) ₄

CH _(CH3) (CHgJgO (CH _{2) 4}

CH (CgH ₅ ) (CH ₂ CH (CH ₃ )

(CHg) ₄ O (CHg) ₅

(CHg) ₄ O (CHg) ₅

(CHg) ₈ O (CHg) ₅

(CHg) ₈ O (CHg) ₅

(CHg) ₈ O (CHg) ₅

(CHg) ₈ O (CHg) ₅

OCH (CH ₃ ) (CHg) ₃

OCH (CH ₃ ) (CHg) ₃

OCH (CH J (CH ₂ )

OCH (CH) (CHg) ₂

4-Pyridyl 3-Pyridyl 4-Pyridyl 4-Pyridyl 4-Pyridyl 4-Pyridyl 4-Pyridyl 4-Pyridyl 4-Pyridyl 4-Pyridyl 4-Pyridyl 4-Pyridyl 4-Pyridyl 3-Pyridyl 2-Pyridyl 2-Pyridyl 2- Pyridyl 4-Pyridyl 4-Pyridyl 4-Pyridyl 4-Pyridyl 2-Pyridyl 4-Pyridyl 4-Pyridyl 4-Pyridyl 4-Pyridyl 4-Pyridyl 4-Pyridyl 4-Pyridyl 4-Pyridyl 4-Pyridyl 2-Pyridyl

X

1 2 3 1 2 1 2

1 2 1 2 1 1 2 O 3 1 1 1 1 1 O O 23 1 3 2

~ 2-

H H H

CH,

H H

CH]

0 (CHg) ₂

OCH (CgH ₅ ) (CHg)

 2'5

g) ₂

CH (CH ₃₎ CH (CH ₃₎ (CHG) ₅ CH (CH ₃₎ CH (CH ₃₎ (CH ₂₎ CH (CH ₃₎ CH (CH ₃₎ (CHG) ₅ CH (CH ₃₎ CH (CH ₍₃₎ CH _{2) 5} CH (CH ₃₎ CH (CH ₃₎ (CHG) ₆ CH (CH ₃₎ CH (CH ₃₎ (CHG) ₆ chgo (CH ₂₎

CHgO (CIIg) ₂ CH (CH)

gO (CIIg) ₂

Chgo (CH ₂₎

chgo

Chgo (CHG)

CH (CH ₃₎ CH ₂ O (CHg) ₇

CH (CH) CH ₂ OCH (CH) CH ₂

2 ^; 6 2 '

CH (CH ₃ ) CH ₂ O (CH.

CH (CH ₃₎ CH ₀ O (CK ₀₎

CH (CH

CH (CH ₃ ) CH ₂ O (CH ₂ ),

CH (CH ₃₎ CH ₂ OCH (CH.

CH (CH ₃ ) CB ₂ O (CH ₂ ) ₇

CH ₂ CH (CH ₃ ) O (CHg) ₂ -

CHgCK (CH ₃₎ OCH (CHy CHg) ₂

4-pyridyl

4-pyridyl

3-pyridyl

3-pyridyl

4-pyridyl

2-pyridyl

H-

^C 6 ^H 5 H

^C 6 ^H 5 4-FC ₆ H ₄

H H

^C 6 ^H 5 4-ClC ₆ H ₄

^C 6 ^H 5

H H H

4-pyridyl H

- [^ p-EcrAi-s ^ ( ³ HO) ³ HD-HO ³ HO C ^ H ⁹ O , ^C ( ³ HO) (^ HO) HDO ³ HO = HD ³ HO C H ^ ( ³ HO) ³ HO = HD ³ HO C ³ HO , H ^ C ³ HO) O ^ ( ³ HD) = H0 ³ ( ³ HD) ³ HO H ⁹ ( ³ HD) 0. = Η0 ^ ( ³ Η0) ¹⁷ H ⁹ OID-I? ^C ( ³ HD) (^ HD) HO ³ HO = HD ³ HO Z T ^ PT ^ -tz ³ Η0 (^ Η0) Η0 (^ HO) HO ³ HO = HD ³ HO X ^ H ⁹ O ( ^C HD) H00 ^C ( ³ HD) = HD = H0 ³ H0 I ³ HO ^ H ⁹ O ³ HOO ⁵⁵ HO ¹⁷ C ² Hp) U ^ H ⁹ O ^ ( ³ HD) (^ HO) HD ³ HO = HO ³ HO I / H ^ ( ³ Η0) ³ ( ^ε Η0) 0 ³ HD = HD- ³ HO \ H ³ H0 ³ (^ HD) O ^ ¹ E ⁹ QV I " ¹⁷ H ⁹ Oa- !? ³ ( ³ HD) ( ^C HD) HDO ι ^ H ⁹ O ¹ ( ³ Η0) (^ Η0) Η0 • ^C H0 I H ^ ( ³ H0) ³ (Sl0) 0 ^ HD I Tüp-tJ ^ j-t / ^ζ ( ³ Η0) 0 ⁸ ( ³ Η0) ⁵ H ⁹ O I ^ h ⁹ o ^ ( ³ HD) (^ H0) HD0 ⁵ H ⁹ D ί H ⁹ ( ³ HD) ³ ( ^€ H0) 0 ⁵ H ⁹ O Z H ^ ( ³ HO) (^ H0) HD (^ HD) HO ⁵ H ⁹ O 0 H ⁹ ( ³ HO) ³ (^ HO) O ⁵ H ⁹ O ι ^ H ⁹ O ^ ( ³ HD) (^ HD) HO ⁵ H ⁹ D ι H ³ ( ³ HD) (^ HD) HOOC ^ HO) HO ² HO I BIMIH

- 88 -

Example 11

The benzyl ethers of Example 10 are catalytically hydrogenated according to the procedure of Example 2 to compounds of the formula given below, where X, Rp, Z and W are as defined in Example 10.

QH ' ZW

Ex iel 12

The chemical and then catalytic reduction of the compounds of Example 10 according to the procedure of Examples 3 and 4 yields compounds having the formula given below wherein the variables X, Rp, Z and W correspond to the definition in Example 10. In any case, the cis and trans isomers are generated.

Z-w

Example 13

The compounds named below are prepared according to the procedure of Example 5 from suitable 3-alkoxy-2-cycloalkene-1-ones and appropriate 2-benzyloxy-4- (Z-W) -bromobenzenes ,,

Z-W

X Ε. Z W 1 G (GH ₃ ) ₂ (CHg) ₆ H 1 ¹ " ^υ 3 7 G (GHo) p (CHp) _fi H 1 0 (CH ₃ ) ₂ (CH ₂ ) ₆ H 1 H OCH (CH ₃ ) (CH ₂ ) ₃ O ₆ H ₅ 1 H (CH ₂ ) C H. 1 CHO (OHG) ₁₃ H 1 CH ₂ C ₆ H ₅ 0 (CH ₂ ) ₄ · 4-FC ₆ H ₄ 1 (CH 2) ₄ C ₆ H ₅ 0 (CH ₂ ) ₁₀ 4-ClC ₆ H ₄ 1 HC ₆ H ₁₃ OCH (CH ₃ ) (CH ₂ ) ₃ 4-FC ₆ H ₄ 1 tC ₄ H ₉ (CH ₂ ) ₃ O (CH ₂ ) ₈ H O H C (CH ₃ ) ₂ (CH ₂ ) ₆ H O CH ₃ OCH (CH ₃ ) (CH ₂ ) ₃ O ₆ H ₅ O Yes-G ₃ H ₇ , 0 (CH ₃ ) ₂ (CH ₂ ) ₆ H O Yes-O ₆ H ₁₃ (CH ₂ ) ₆ 0 ° 6 ^H 5 O (CH ₂ ) ₂ C ₆ H ₅ C (CH ₃ ) ₂ (CH ₂ ) ₂ O (CH ₂ ) ₂ f ^H O 1-C ₃ H ₇ O (CH _{2) 1O} 4-ClC ₆ H ₄ 2 H (GH ₂ ) ₅ H 2 H H 2 OH ₃ O (CH ₂ ) ₁₃ C ₆ H ₅ 2 C ₂ H ₅ GH (CH ₃ ) (OH) ₂ O G _{6 5} K 2 00 (CH ₃ ) ₂ (CH ₂ ) ₅ H 2 ^CH 2 ° ^6H 5 (GHg) ₆ O (OH) ₇ H 2 (GH ₂ ) ^ O ₆ Hc CH (C ₂ H ₅ ) (CHg) ₂ 4-ClCrH ,, O H- 3 H CH (CH ₃ ) (OH) ₄ ' O ₆ H ₅ 3 CH ₃ OCH (CH ₃ ) (CH ₂ ) ₆ 4-FC ₆ H ₄

Vo - ^ζ ( ² HD) (^ HO) HOO ² HO = ICT ^- ( ² HO) ¹⁷ H ⁹ OTO- ^ ^ζ ( ² HO) (^ HO) HO ² HO = HD ² HO

J -ρ? C -ρ "ρ

νΆκ) JVHiJJiJ Ü.Uilvy Jtlky

H ^ (

HC HOy ¹ HQ ~ "U

¹⁷ H ⁹ D, !! -! / ^C ( ² H0) ( ^C H0) H0 * ⁶ H ¹⁷ OT U

V xliJ ^ V riiJO Vo I / H ^ ^U ( ² H0) Vo C H ^ ( ² HO) (^ HO) HO - [üp-Ueji ^ -iy ^ ( ² HO) (^ HO) HOO Vo Vo ^ C ² HO) Vo O H ⁹ ( ² H0) ² (^ HO) O ^ H ⁹ O ² HO t / H ^ ( ² HO) (^ HO) HOO Vo ² HO ι Vo ⁹ ( ² Η0) ² (^ Η0) 0 α _Η 9 ₀ _ _π ι • H ^a ( ² H0) Vo ζ - [UpT ₁ i ^ iI ₇ ^ ( ² H0) ( ^C H0) H0 H ζ O ¹⁷ C ² HO) ^ • HO ί ^ ( ² HO) O ^ ( ² HO) Vo-T Z - [^ p ^ M i-i? ⁸ ( ² HO) O Vo ^C ( ² HOs) Z - [üpTcci ^ - ^ ² ( ² H0) H Z O ^ ^U ( ² HO) ^ H ⁹ O ² HO Z TÜpl-JCAi-i; ^ ( ² HO) - ^ H ^ O-T ' Q T ^ ^ PTJ I-i; . ^ ( ² HO) (^ HD) HO H O , "C ^ -C ^ PTcci ν HO / U v, HD / £ ^ h ⁹ o- ^   ο TÜpTJ ^ -s H ι lüp-cjr ^ i-v ^{C (2} H0) (^ HO) HOO t / i> _H £ ₀ _ _n ι I ^ ^ j ^ PTJ • ^ ( ² HO) ( ¹ HD) HO Vo ^ ( ² HO) I / lüpxccAi-iy ² ( ² H0) O ^Ol - ( ² H0) ί H ² ( ² HO) ² (HO) O ζ H O ^ ^U ( ² HO) Vo

~ 92 ~

1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 3 3 3 3 3

(CH ₂ ) CHCH = CH ₂ CH ₂ CH = CH-CH ₃ (CH ₂ ) ₂ CH = CH-i-CH ₂ CH-

^CE 2 ^C 6 ^H 5

CH

'6 ^H 5

CH ₂ CH = GH ₂ (CH ₂ ) 1 CH = CH ₂ CH ₂ CH = GH ₂ CH ₂ C ₆ H ₅

"Γ7

CH ₂ CH = C (CH ₃ ) ₂

0 (CH ₂ ) ₁₀ O (CH ₂ ^

(CH ₂ ) ₃ 0CH ₂ 0 (0Η ₃ ) ₂ (0Η ₂ ) ₆ CH (CH ₃ ) (CH ₂ ) ₂ C (0H ₃ ) ₂ (CH ₂ ) ₇ CH (CH ₃ ) (CH ₂ ) ₃ C (CH ₃ ) ₂ (CH ₂ ) ₆ OCH (CH ₃ ) (CH ₂ ) ₃ (OH ₂ ) ₅

(CH ₂ ) ₁₂

CH (CH ₃₎ CH (CH ₃₎ CH ₂ (CH _{2) 3}

0 (CH ₂ ) ₂

CH (CH ₃₎ (CH _{2) 3} (CHG) ₆ OOH. ₂ CH (CH ₃ ) CH (CH ₃ ) (GH ₂ > ₅ CH ₀

2-pyridyl

H H H

3-pyridyl

2-pyridyl

4-pyridyl

4-01O ₆ H ₄ H

C ₆ H ₅ H

The catalytic hydrogenation of the above compounds according to the procedure of Example 2 yields the corresponding phenol compounds.

example

It is worked according to the procedure of Example 6, however, the appropriate 3 ™ Z ^ ~ ^ ^e ^ ^z y ^ ⁰ ^ ~ ^^ ~ ¹ ^) P ^ ^ERL yi7 ^c y ^c ^ - ⁰ ~ alk-2-enone and (C 1 -C 10) CuLi was used to produce the following compounds and the corresponding 1,2-addition product

207 799

z ~ w

OH ₃ 1 -O ₃ H ₇

CH

₉ CH ₂ O ₆ H ₅

Ij-C ₄ H ₉

CH ₃

H H

CH ₃ GO ₄ H ₉

CH ₃

XO ₃ H ₇

CH

CH "CH

CH ₃ CH ₃ CH ₃ CH ₃ CH ₃ OH ₃

CH CH

CH-CH "

ch '

CH ₃ CH ₃ CH ₃ CH ₃

CH

"3

₃₂₂₆ C (CH ₃ ) ₂ (CH ₂ ) ₆ C (CH ₃ ) ₂ (CH ₂ ) ₆

₁₃

C (CH _{3) 2} (0H _{2) 6} 0 (CH _{2) 4} 0 (0H _{2) 10} (CH _{2) 3} O (CH _{2) 8} O0H (CH ₃₎ (CH _{2) 3} C (CH _{3) 2} (CH ₂ ) ₆ OOH (CH ₃ ) (OH ₂ ) ₃ C (CH ₃ ) ₂ (CH ₂ ) ₆

(OH ₂ ), (OH ₂ X

₂₁₃ O0 ₍₃ 0H) ₂ (0H _{2) 5} (CH _{2) 6} 0 (0H _{2) 7} () ()

₂₅₂₂ 0H (0H ₃ ) (0H ₂ ) ₄ 0OH (OH ₃ ) (OH ₂ ) ₅ (CH ₂ X, OO 0 (CH ₃ ) ₂ (OH ₂ ) ₂ (CH ₂ ) ₁₀ O (CH ₂ )

₂ ) ₁₀

4-PO ₆ H ₄ 4-01C ₆ H ₄

° 6 ^H 5

^C 6 ^H 5

H H

° 6 ^H 5 H

H 4-01O ₆ H ₄

4-PO ₆ H ₄ ^C 6 ^H 5 H

 I I Il III

1 1 1 O O 2 2 3 3 1 1 O 2

V /

ΐ-

CH. CH "

"Γ7

CH.

1-CH ₃ H ₇ H

OCH (CHO) (CH ₂ ). (CH ₂ ) ₁₃ CH (CH ₃ ) (CH ₂ ) ₃ (CH ₂ ) ₇ (CH ₂ ) ₂ O (CH ₂ ) ₈

CH ₂ C ₆ H ₅

CH, CH *

CHO OCH (CHO) (CH.

CH "CH"

ch!

5 ° 6 ^Η 5

CH '

₃₂₃ C (CH _{3) 2} (CH _{2) 6} C (CH _{3) 2} (CH _{2) 6} OCH (CH ₃₎ (CH _{2) 3} 'CH (CH ₃₎ CH (CH ₃₎ (CH ₂ 0 (CH ₂ ) ₄

4-pyridyl-pyridyl 4-pyridyl 3-pyridyl 4-pyridyl 4-pyridyl-2-pyridyl-3-pyridyl-pyridyl

° 6 ^H 5 H

^ Pyridyl H

By catalytic hydrogenation of the above compounds according to the procedure of Example 2, the corresponding phenolic compounds are recovered.

Example 15 -

3 .- / 2JU (1,1-di-ethylheptyl) -2-hydroxyphenylT'-2-cyclohexenol . 1.00 g (3.18 mol) of solution at -3O ⁰ C

, 1-dimethylheptyl) -2-hydroxyphenyl7-2-cyclohexenone in 60 ml ether was tropfenweise'6,3 ^ l of a 1 M solution of diisobutylaluminum hydride (in toluene) The reaction mixture was stirred at -3O ⁰ C for 30 minutes and then to 1.5 liters of water. The quenched solution was extracted with three 400 ml portions of ether, and the combined extracts were washed twice with 125 ml of saturated sodium chloride and dried over magnesium sulfate. After evaporation, the crude product was using

-95- 207 7

column chromatography on 50 g of plaque eluted with ether to obtain an oil. Crystallization of the oil from pentane gave 256 mg (25%) of the title product.

Melting point: 87 to 88 ⁰ O.

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

PMR: <T 5JJjJo ₁ 0.83 (m _f terminal methyl), 4.37 (m, carbinol-methine), ^3. 5 .9 O (m, vinyl H). _s 6.37 OvOH) and 6.87 (m, ArH), analysis: Calculated for C21 ^H 32 ° 2 ^{: G} * 79 »70; H, 10.19%. Found: 0, 79.68; H 9,96 %.

The phenolic compounds of Examples 15 and 14- are reduced following the procedure of Example '$' to obtain the compounds listed below in which the variables have the meanings given in Examples 15 and 16. The dashed line represents a double bond (products of Example 15), in which case R 1 is absent _#

Z-W

Example 16

Ί-Dirnethylhepty1) ~ 2-hydrosyphenyl7-3-

äth ylenketyl

A solution of 500 mg (1.59 mmol) of 3- / 5 "(1,1-dimethylheptyl) -2-hydroxyphenyl 7-2-cyclohexenone, 7.8 g (127 mmol) of ethylene glycol, 375 mg (3.18 mmol) Hydroquinone and 50 mg (0.263 mmol) of p-toluenesulfonic acid monohydrate in 50 ml of benzene were refluxed for 12 hours using a molecular weight analyzer of 3A molecular weight.

The reaction mixture was cooled and added to 500 ml of saturated sodium hydrogengenoarbeneate. The quenched mixture was extracted with three 150 mL portions of ether, dried over magnesium sulfate and evaporated to a solid. This solid was purified by column chromatography on 50 g of silica gel eluting with 50% ether-petroleum ether to give (after crystallizing from pentane) 393 mg (69%) <les u ite product * Melting point:? 97 to 9.8 ⁰ O

MS: m / e 358 (M ⁺ ), 297, 273, 245 and 229.

₃ 0.88 (m, terminal methyl), 1.29 (s, according to dimethyl), 1.85 (m, methylene), 2.50 (m, two methylenes), 4.03 (s, ethylene ketal), 5.62 (s, OH), 5.84 (m, vinyl H), 6.83 (m, ArH), and 7.02 (d, J = 8Hz, ArH).

Analysis: Calculated for C ₂ -JU ₂₄ Oo: 0, 77.05; H, 9.56%. Found: 0, 76.98; H, 9.42% «,

Repetition of this procedure using the cycloalk-2-enones of Examples 5, 7, 13 and ethylene, propylene or butylene glycol gives the corresponding cycloalk-3-enone alkylene ketals of the compounds.

Bei p iel 17

3- / 4 ^ - (1,1-dimethylheptyl) -2-hydroxyphenyl) -4-methylcyclohexene

3 ~ enon ·

A mixture of 4.08 g (0.1 mol) of J> - /% -A, 1-dimethylheptyl) -2-hydroxyphenyl 7-4-methylcyclohex-3-enone ethylene ketal, 50 ml of 2N oxalic acid and 50 ml of methanol became 6 hours stirred at 25 ⁰ C. The reaction mixture was added to 500 ml of water / 250 ml of ether. The ether extract was washed once with 250 ml of saturated sodium chloride, dried over magnesium sulfate.

dried and evaporated. The residue was purified with the aid of _: column chromatography on 400 g of silica gel while bleeding with 50 % ether-pentane to give the titer compound. The remaining ketals of Example 6 are converted to the ketone form in the same manner. ,

Example 18. · ',.

₁ 1 - .Dimethylh eptyl) -2 ~ hydrpxyp henyl7oyclo hex-3-en-1 - ol having To a solution of 17.5 -1S ⁰ O S (50 mmol) of 3- ^ - (1,1-dimethylheptyl) 2-Hydroxyphenyl-7-cyclohex-3-enone in 50 ml of methanol was added 1.9 g (^ 0 mmol) of sodium borohydride. The reaction mixture was stirred for 30 minutes and then added to 250 mL of saturated sodium chloride / 250 mL of ether. The ether extract was washed 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 50 % ether-pentane to give the title compound.

Similarly, reduction of the remaining ketones of Example 1 $ yields the corresponding gyclalk-3-ene-1-ols.

• Example 19

ß- / 4% * (1 «1 -Dime thy lheptyl) -2-hydroxyphenyl7cyclohex ~ 2-en-1-ol To a -18 ⁰ O having solution of 70.0 g (0.20 mol) 3- ^ 4- (1,1-Dimethylheptyl) -2-hydroxyphenyl-7-cyclohex-2-enone in 200 ml of methanol was added 7.6 g (0.20 mol) of sodium borohydride. The reaction mixture was stirred for 30 minutes and then added to 1 liter of saturated sodium chloride / 1 liter of ether. 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 30% ether-pentane to give the tite compound.

In a similar manner were prepared by reduction of 3- / T- ² (Z - /?) 2-Hydroxypheny.L7cycloalk ~ 2-enone from the examples. 7 Compounds obtained with the formula:

where X, ϊ? 2 » ^z and W correspond to the definition given in these examples. ,

Example 20

The procedure of Examples 18 to 20 was repeated, but the appropriate 3-Z 1 - (ZW) -2-hydroxyphenyl-7-cycloalk-2-enones of Examples 15 and 46 were obtained to give compounds of the following formula wherein X ₁ , Z and W correspond to the definition given therein.

2-W

Example 21

3- / 2 "-acetoxy-4 - (1-i-dimethlylheptyl) -phenyl 7-cyclohexanone A solution of 2.0 g of 3 -, / 2" - hydroxxy4- (1,1-dimethylheptyl ) phenyl7 ^c yclohexanon is dissolved in 15 ml of pyridine at a temperature of 1O ⁰ O with 10 ml Essigsäureanhydrid.behandelt, and the mixture is stirred for 18 hours under nitrogen, inschließend it is poured onto ice / water and acidified with dilute Ohlorwasserstoffsäure. The acidified mixture

-99- 207 79 9

is extracted with ethyl acetate (2 × 100 ml), the extracts are taken together, washed with brine and dried (MgSO 4). By evaporation under reduced pressure. the title product is obtained in the form of an oil.

Similarly, the other phenol compounds of formula IA-ID of the present invention are converted to their monoacetoxyesters (the phenolic hydroxy group) and converted to the corresponding ester derivatives by substituting "the anhydrides of propionic, butyric and valeric acids",

Example 22.

1 ~ Aoetoxy-3 ~ / ^ '- acetoxy-4- ^ - (g-phenyl) entr / loik cyclohexane To a solution of 2.0 g of 3-Z-hydroxyethyl 4 - (2 -. 5-phenyl) pen tyloxy ~.) phenyl7cyclohexanol in 20 ml of pyridine at a temperature of 10 ⁰ O, 20 ml of acetic anhydride, and the mixture was stirred for 18 Stunden.lang under nitrogen. then, it was poured onto ice / water and with dilute The product was isolated by extraction with ethyl acetate (2 x 100 ml) and the combined extracts were washed with brine, dried (MgSO4) and evaporated to give the diacetyl derivative as an oil.

In the same way, the compounds of formulas IA-ID, wherein B is hydroxy or hydroxymethyl and R 1 is hydrogen, have been converted to their diacyl derivatives. By replacing the acetic anhydride with propionic, butyric or valeric anhydrides, the corresponding diacyl derivatives result,

Example 23

3 ^ / 2 "- (^ Ηο ^ ηο1χηοΌυ: ^: Ε'γ1οχγ) -4 (1,1-dimethylheptyl) phenyl7cy-

clohexanol

, - 100 -

Dicyclohexylcarbodiimide (0.227 g, 1.1 nmol) and 4-H-Piperidylbuttersäurehydrochlorid (0.222 g, 1.0 mmol) are added to a solution of 3-Z ^ - ^H yäroxy-4 - (1, 1-dimethyIheptyl) phenyl7 cyclohexanone (0.300 g, 1.0 mmol) in methylene chloride (25 mL) at room temperature. The mixture is stirred for 18 hours, then cooled to ⁰ ° C. and filtered. Evaporation of the filtrate gives the title product in the form of its hydrochloride salt. "

Similarly, the reactant of this example and the other 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, j component has the following values are prepared:

H) \

₂₂₄₉₂

-CO (CH ₂ ) pN- (methyl) piperazino -COC (OH ..) ₂ (CH ₂ ) ₂ -piperidino () ()

₂₃₂₅₂ -COCH (CH ₃ ) (CH ₂ ) ₂ -morpholino

-CO (CH ₂ ) n -pyrrolo.

-CO (CH ₂ ) -v-pyrrO 1 idino

-COCHg-pyrrolo.

-CO (CH ₂ ) ^ - piperidino-CO (CH ₂ ) ₄ NH ₂ -CO (CH ₂ ) TH TH (C ₃ H ₇ ) -C / (CH ₂ ) ₂ -H-butylpiperazino

Careful neutralization of the hydrochloride salts gives free basic esters which are converted to other acid addition salts by the procedure of Example LS .

The hydrobromide, sulphate, acetate, malonate, citrate, glycolate, gluoconate, succinate, sulfosalicyrate, and tartrate salts are produced in this vein »

Ex iel24

3- / 2-Hydoxy-4- (1,1-dimethyl-thyphenyl ) -phenyl 17-1 -methylene cyclohexane *

To a 50% sodium hydride / mineral oil mixture (2,2s g, 48 mmol) (3 se 25 ml portions of pentane washed) 90 ml of dry dimethyl sulfoxide are added, and the mixture is kept at 7O ⁰ C for 3/4 hour , 17.79 S (51 in mol) of methyltriphenylphosphonium bromide are then added in one portion. The yellow solution is stirred at 25 ⁰ O for 30 minutes, and then be (mlvlol 6.3) 3 ~ at once 2.26 g | F acetoxy-4- (1,1-dime thy lheptyl ^ henyl / cyclohexanone dissolved in 90 ml DimethyIsulfosid added, and the mixture is further maintained at 63 to 65 ⁰ O 1 1/2 hours. the reaction mixture is then poured onto 150 ml of ice / 25 g NaHCOo and extracted with 3 x 50 ml ether. the taken together ether extracts over MgSO _2, dried, stained with charcoal and filtered through a pad of silica gel to obtain a colorless oil which on 73 S silica gel (EIuierung with solvent cyclohexane) is chromatographed. First, a non-polar impurity was eluted then the polarity of the solvent is increased to ither / cyclohexane (1:10) to give the title compound as a colorless oil. "

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

- 102 Example 25

! 'A in 25 ml dry letrahydrof uranium dissolved solution of 1.03 g of 3-Z ² "- ^H y y ^{DROX Zj} ~ Ci, 1-diniethylheptyl) phenyl7-1-methylene-cyclohexane (3 mmol) is cooled in an ice / Water bath cooled to ⁰ ° C. Boraii-tetrahydrofuran-koiaplex (4.5 mL, 4.5 mmol, 1 M 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 reactant, stirred for 15 minutes, then 3 ml (9 mmol) of 3N sodium acetate are added followed by 3 ml of 30% hydrogen peroxide is stirred for 15 minutes at ⁰ ° C., then allowed to warm to room temperature and stirred overnight (24 hours), poured onto 100 ml of ice / water, then extracted with 3 × 50 ml of ether washed with sodium sulfite until negative in the starch KI test are dried over MgSO 4 and evaporated to dryness to give a light yellow oil which is chromatographed on 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 cycloalkenones of Example 2k are converted to the corresponding hydroxy methyl derivatives.

- 207

Example 26

3- / 2-Benz y 1 oy / - ^ · (Ζ-ΐ /) phenyl 17-5-R /, - cyc 1 oheρtome and - c yclooctenone

Following the procedure of Example 5, the following compounds are prepared from appropriate 3-alkoxy-2-cycloalkene-1-ones and 2-bromo-5- (Z-W) phenol benzylators

--104-

¹ Cw *

a ¹⁰

tPv r-4

ta O

\ Ω Ι

Ό W 4 "

.! - Jl-Il-I

^ h> t> s

^r C> ^Γ Ο TlJ

• Η -Η -H

VD O

Ol O ί

4-> 5

to W VD-H VD VOO U LPVO OH

3 'Jx ,. Pq O

^ ⁰ T

P3!

VD

OJ OJ cn LPv LPv

O OJ OJ OJ OJ

cno ο woo

ο / 'O O vv ν. /

- ^ o oo cno ο ο

ν /> / ~ ν txj cn cn ν " ^{£ Υ} ^ vD VD ν * vD 4" CO

OJ OJ OJO M trj / "^ ^^ / -S. ^ - N / ~ \ /" Ν / ~ \ / -N

iUUj ^ - 'OO OJ CM OJ OJ OJ. OJ-OJOJ

^^ ^ -J ^ * 1 i ^^^ ^ M ^ II _m | ι II i J ι IIIIJ j ₁ j * II II I *!

»- '-V- / V O O IxJ OO O O O OO O O O O Ov> v> v ^ / s_xv- / v> .w ^

CN

LT \

LTvn LP \

} rj O cn cno <^

OJ I! UWIWK OJ IO · Η OO Λ Ό OO Cl

LT OJ

CtN CJ

ο o

I i

LPV

cno cn cn

ι? j, M i4. O Ö. OO

WOJOJOJOJOJOJOJOJCVIOJOJOJOJ

id W W

LPV

ο W

lpv cn ^/ " ^N » to

OJO t

LP »

VD o W

KO ^ S) \ Ω (Ω

CM OJ OJ OJ

OJ OJ OJ OJ

cn cn cn cn ο o

OJ

cn

/ "Ν ν" cn / * " ¹ * lpv cn v- v-

tC!

δ oi ^ S v _ »/ ν- / v> v_ / MOW O Ό O O O w ο

OJ OJO W "W K

W K ν- / ο O O

OO ^- WW w v_ /

v ^ V- ^ O O O O

VD VD CVI World Championship OJ Ol

ww on w

O O vv O O

oj oj oj ^ cn cm Oj (T ^ cno cn cn

OO

Mt

cn v-cn

V-CN CNv CTn v-

W W W tu ϊ - ^ - l fcd

Lf \ vDcn (Λ ία lt \ 4-LPvvD o o cno ο cntrj cno W ο

W OJ I JW! IW OJ W I vD I

oo d-HOfi dooo oo α

LT \

cn cnjx | SxJ W oj

O O O

OJ OJ CM CM

OJ

ojojojojojojojojojcncn

2L

3 - -Ί / ΊΤΤ C (CH ₃ ) ₂ (CH ₂ ) ₆ H 3 1-C ₃ H ₇ J Λ! TT C (CH ₃ ) ₂ (CH ₂ ) ₆ H . 3 ch / HC ₆ H ₁₃ C (CH ₃ ) ₂ (CH ₂ ) ₇ H 3 HC ₃ H ₇ CHO C (CH ₃ ) ₂ (CH ₂ ) ₇ •H 3 Ö I "j CH (CH ₃ ) (CH ₂ ) ₄ H 3 CH ₃ (CH ₂ ) ₅ H 3 CH ₃ (CH ₂ ) ₅ H 3 CHO (CH ₂ ) _g H ' 3 / TTJ (CH ₂ ) ₁₃ H . 3 C ₂ H ₅ CH (CH ₃ ) (CH ₂ ) ₂ ° 6 ^H 5 3 CH ₃ CH (CH ₃ ) (CH ₂ ) ₃ 4-FC ₆ H ₄ 3 nC ₄ H ₉ CH (C ₂ H ₅ ) (CH ₂ ) ₂ 4-ClC ₆ H ₄ 3 CH ₃ OCH (CH ₃ ) (CH ₂ ) ₃ . C ₆ H ₅ 3 CH ₃ 0CH (CH ₃ ) (CH ₂ ) ₆ 4-FC ₆ H ₄ 3 C ₂ H ₅ 0 (CH ₂ ) ₄ · C ₆ H ₅ 3 HC ₅ H ₁₁ O (CH _{2) 1O} 4-ClC ₆ H ₄ - 3 CH ₃ OCH (CH ₃ ) (CH ₂ ) ₃ 4-pyridyl 3 CH ₃ 0 (CH ₂ ) ₅ 3-pyridyl 3 CH ₂ O (CH ₂ ) ₅ 4-FC ₆ H ₄ 3 CH (CH ₃ ) CH ₂ OCH ₂ 4-ClC ₆ H ₄ 3 (CH ₂ ) ₈ O (CH ₂ ) ₅ 4-pyridyl 3 (CH ₂ ) ₃ 2-Pyridy l- 3 (CH ₂ ) ₃ 0 4-pyridyl

The catalytic hydrogenation of the abovementioned compounds by the procedure of Example 3 gives the corresponding phenol compounds.

Example 2?

tr ans-3- / ¹ T- (1,1-dimethyl thyheptyl) -2-hydroxyphenyl 17-4- (2- .propenylcyclohexanone

((2 ~ propenylCyclohexanol 2.15 _g} 6.03 mmol) to a solution of 3- / 4-0.1-dimethylheptyl) -2-hydroxyphenyl74-, (mixture of isomers) in dichloromethane (15 ml) was added pyridinium chlorochromate ( 2.59 S> 12.1 mmol) The reaction was stirred at room temperature for 2 hours, diluted with ether, diatomaceous earth was added (?) And the mixture was filtered through magnesium sulfate). The evaporated filtrate was collected by column chromatography

Purified 200 g of silica gel with blueing with 20 % ether-pentane to give 250 mg of crude title compound. This was further purified by preparative thin layer chromatography on two 20 cm χ 20 cm χ 2 mm silica gel plates eluting 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 . MS: (m / e) 356 (H ⁺ ), 34-1, 338, 314-, 288, 271, 257, 253 and 229.

HIR: cf ^ ₁ 0.79 (s, terminal methyl), 1.22 (s, gem dimethyl.), ^4,8-3 5,2 and 5,4 - 6,1 (n, vinyl H), 6.7 (η, ArH) and

6.82 (d, J = 8 Hz, ArH).

Analysis; Calculated for C ₂₄ H ₃₆ O _2: G, 80.85; H, 10.18 %

Found: C, 80.92; H, 9.86 ^.

Example 28

5 ~ / 2 "-benzyloxy -4 ~ (1" 1- dimethylheptyl) phenyl7-3,4-diynethyl · 2-cyclohexen-1-one

Following the procedure of Example 1, 5-Z, 2-benzyloxy-4- (1,1-dimethyl thyheptyl) phenyl 7-3-me thoxy-e-methyl-H-cyclohexene-1-one is obtained from Grignard Reaction with methyl magnesium to give the title compound.

Debenzylation of the product obtained by the procedure of Example 2 gives the corresponding phenol.

The following compounds are thus obtained from suitable compounds and suitable Grignard reagents RJJLgI:

PK

Z-w

where R _{2 is} ¹ , Z and W are DEF definition \ ' and R 1 is methyl, ethyl, n -propyl, i -propyl and n -hexyl.

Example 29

3- / 2 "-Hy dro xy-4- (1,1-dimethyl thyheptyl) phenyl7- ^z i- _< 5-dimethylcyclohexanol

The debenzylated compound of Example $ β is named after

procedure of Example 3 with sodium borohydride to obtain the Tite! reduced compound,

Similarly, the remaining compounds of Example 2o 'are reduced to the corresponding cyclohexanol derivative.

- no - 907 79 9

Example 30 General picture 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 recrystallized from a suitable solvent, e.g., B, methanol-ether (1:10).

Similarly, the hydrobromide, sulfate, nitrate, phosphate, acetate, butyrate, citrate, malonate, maleate, fumarate, malate, glycolate, gluconate, lactate, salicylate, sulfonyl salicylate , Succinate, pamoate, tartrate and embonate salts.

799

Example 31

cis -3- / 4 - (1 _t 1-dimethylheptyl) -2-hydroxyphenyl 7-cyclohexane ol

2 ^t -0-hemis-X-Lucinate sodium salt

To a solution containing O ⁰ G of 1.00 g (3.14 "DMoI) cis-3-ZZL (1 ₎ 1-dimethylheptyl) -2-.hydroxyphenylcyclohexanol in 3 ml of dichloromethane is added 0.383 S (3.14 mmol) 4 To the resulting solution is slowly added 0.314 S (3.14 mmol) of succinic anhydride in 1 mL of dichloromethane The reaction mixture is stirred at ⁰ ° C for 4 hours, then 3.14 mL of 1 N hydrochloric acid are added slowly The reaction mixture is stirred for a further 5 minutes and then 100 ml of water are added to 100 ml of dichloromethane The dichloromethane extract is dried over magnesium sulfate and evaporated 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 was recovered.

By means of this procedure, the other compounds described herein are converted to their hemisuccinate esters,

Example 32

cis-3 /% - (1,1-dimethyl thyheptyl) - 2-hydroxyphenyl-7- cyclohexanol

2 ^f - »0-phosphate ester ammonium salt

To a O ⁰ G-containing slurry of 0.126 g (3.14 mmol) of potassium hydride in 3 mL of dimethylformamide is added a solution of 1.00 g (3.14 mmol) of cis-3-Z 1 ( ¹ , 1-dimethyl thyheptyl ) -2-hydr oxyphenyl7cyclohexanol in 3 ml of dimethylformamide. To

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 to become 3, 14-nl 1N sodium hydroxide in ethanol The addition of ether leads to crystallization of the product, recrystallization from ethanol then gives the title compound.

Similarly, the other compounds described herein will be converted into their phosphate ester sodium salts and by exchanging

Sodium hydroxide converted to potassium hydroxide in their corresponding potassium salts. ·

Example 33 ·

100 mg of 3-Z 1 -d, 1-dimethylheutyl) -2-hydroxyphenylcyclohexanol 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 34-

A tablet base is prepared by mixing the ingredients below: sucrose 80.3 parts

Tapioca starch 13.2 parts magnesium stearate 6.5 parts

Into this base is added sufficient tra, Os ~ 3/2-KjdToxy ~ (2 ~ (5-phenylpentylozy)) - phenyl.7cyclohexanol mixed in to make 2'-ablates containing 0.1, 0.5, 1.5 , 10 and 25 mg drug are obtained.

Example 35

Suspensions of 3- / 3- (- ^/ , 1-dimethyl thyheptyl) -2-hydroxyphenyl-7-cyclohexanone are prepared by adding sufficient amounts of the drug to 0.5 % methyl cellulose to give suspensions of 0.05, 0.1, 0.5, 1, 5, tmd 10 mg drug per ml.

Presentation A

2 ~ ( 3 ~ benzyl @ xyphenyl) -2- methylthiolpropionitrile

A solution of 1500 ml methyl bromide-saturated dimethylsulfoxide was co-precipitated with a solution of 295 mg (1.32 mol) of 2- (3-benzyloxyphenyl) acetonitrile in 200 ml of dimethylsulfoxide and a solution. 420 ml of 50% aqueous sodium hydroxide. Driving the above addition (30 minutes) and then for 1 1/2 hour methyl bromide was constantly bubbled through the reaction mixture, the reaction temperature was maintained by cooling with ice to 6 50 ⁰ G · The reaction mixture was added to 2 liters of water / 2 kg of ice and The resulting mixture was 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 as an oil.

PMR: cT-j ^ 1.70 (s, methyl), 5.12 (s, methylene), 6.8-7.5

(m, ArH) ³ and 7.45 (s, PhH). IR: (CHCl ₃ ) 2247, 1616 and 1603 cm ^-1 .

MS: m / e 251 (M ⁺ ), 236, 160 and 91.

Presentation B ₁ .

2- (3-benzyl oxyp henyl) -2-me thylpropional dehy / 3 To a 15 ⁰ C-containing solution of 325 g (1.25 mol) of 2- (3-benzyloxyphenyl) -2-methylpropionitrile in 1.85 liter of tetrahydrofuran were added in the form of a 1.3M solution in hexane 1.6 mol diisobutylaluminum hydride (in which the reaction temperature was maintained at 15 to 18 ⁰ C). The reaction mixture was allowed to come to room temperature and stirring was continued for 2 hours. It was then quenched by the addition of a solution of 170 ml of concentrated sulfuric acid in 670 ml of water (temperature 30 ^° C.). 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 once extracted 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. »

PMRs ^^ C ₁ 1 »43 (s, methyls), 5.08 (s, methylenes), 6.8 -

7.5 (m, ArHf, 7.4 (s, PhH) and 9.55 (s, aldehyde).

IRs (CDCl ₃ ) 1742 and 1613 cm ^-1 .

MS: 254 (IvI ⁺ ), 259 and 91. '

Presentation C

1 "-Benzyl oxy-3- (1» 1 -diynyl-2-hepteny ^) benzene To a 15 ⁰ C-containing solution of 1.8 mol of dimsyl sodium (from ITatriumhydrid and Dirne thyl sulf oxide) in 2 liters of dimethyl sulfoxide. 768 g (1.8 mol) of pentyltriphenyiphoaphonium bromide were added in portions. The resulting slurry was stirred for 15 minutes at 15 to 20 ^° C., after which 315 g (1.24 mol) of 2- (3-benzyloxyphenyl) -2-methylpropionaldehyde were added slowly (reaction temperature: 30 ^° C.). 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 % ether-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 and evaporated to give an oil. Crystallization of this oil from 50% ether-pentane (to remove triphonylphosphine oxide), filtration and evaporation of the filtrate yielded 559 g of oil. The crude oil was purified by column chromatography on 2 kg of silica gel eluting with 20 % hexane-dichloromethane to give 217 g (57 %) of the product as an oil, PEBt: (/ ^ q ₁ 0.75 (bt, J = 6Hz, terminal methyl), 1.1 (m, two ^ side chain methylenes), 1.43 (s > according to dimethyl) 1.60 (m, allylmethylene), 5.09 (s, benzylmethylene), 5.28 (dt,

J = 12 and 6 Hz, vinyl H), 5.70 (dd, J = 12 and 1 Hz, vinyl

H), 6.7-7.5 (m, ArH) and 7.42 (s, PhH). IR: (CHGl) 1610 and 1587 cm "" ¹ .

MS: m / e 308 (M ⁺ ), 293, 274, 265, 251, 239, 225, 217 and 91.

Similarly prepared were 1-benzyloxy-3- ( 1,1 -dimethyl thyloct- 2-enylbenzene (13.5 g, 70 %) from 15.75 g (0.062 mol) of 2- (3-bensyloxyphenyl) "2". methyl-propionaldehyde and 37.5 g (0.0899 mol) of hexyltriphenylphosphonium bromide, the product was an oil.

PMRI d ^ Q ₁ 0.78 (m, terminal side-chain methyl), 1.40

(s, according to ³ dimethyl), 4.97 (s, benzylethermethylene), 5.23 (m, vinyl H), 5.57 (d, J = 11 Hz, vinyl H) and 6.6-7.4 (m,

ArH and PhH) ... IR: (CHGl ₃ ) 1608 and 1582 em " ¹ .

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

1- »BenzylO3ty -3 ~ (1 ^ 1 ~ dimethyl-2-pr- openyl) benzene as an oil (23.0 g, 91 %) of 2- (3-benzyloxyphenyl) -2-methylpropionaldehyde (25.5 g, 0 , 10 mol) and methyltriphenyiphosphonium bromide (40.3 g, 0.113 mol).

PMR: (. S, gem dimethyl) cf ™ ^ _x 1.40, 4.90 (dd, J = 18 and 2 Hz, vinyl H ^3), 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- (1,1-dimethyl-2-biebyl) benzene as an oil (37.3 g, 77 %) of 2- (3-benzyloxyphenyl) -2-methylpropionaldehyde (46.2 g, 0.182 mol) and ethyltriphtoylphosphonylbromide (75.0 g, 0.202 mol).

- ΛΛΊ - -

PMR: CfMS ₁ ^ _{22 ( djj = 6HZj} vinylmethyl), 1.41 (a, acc.

Dimethyl), 3.503 (s, benzylethermethylene), 5.0-5.8 (m,

nyl H), 6.6-7.5 (M, ArH and PhH). IR: (CHCl ₃ ) 1661, 1626, 1621, 1608 and 1587 cm ^-1 .

MS: m / e 266 (M ⁺ ), 251, 226, 183, 175 and 91.

-n, 1-dimethyl-2-pentenyl) benzene, as an oil (31 g, 74 SS) of .2- (3-benzyloxypropyl) -2-methylpropionaldehyde (40.0 g, 0.157 mol) and propyltriphenylphosphonium bromide ( 66.7 g, 0.173 mol).

IR: (CHCl ₃ ) 1626 and 1600 era "" ¹

MS: (m / e) 280 (M ⁺ ), 265, 251, 237, 225, 211, 189, 147 and 91.

PMR: <f ^ q ₁ 0.62 (t, J = 7 Hz, methyl), 1.40 (s, according to dimethyl), 3.50 (s, benzylmethylene), 5.20 (dt, J = 11 and 7 Hz, vinyl H), 5.59 (dt, J = 11 and 1 Hz, vinyl H) and 6, -6.7.4 (in, ArH).

/ I ~ Benzylo: x: y-3- (1: 1-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 l,

0.173 moles)

IR: (CHCl ₃ ) 1623 and 1600 cm ^-1 .

MS: (m / e) 294 (M ⁺ ), 279, 265, 251, 255 and 91.

PMR: U ^ q ₁ O ₅ 69 (m, terminal methyl), 1.42 (s, according to dimethyl), 3 5.09 (s, benzylmethylene), 5.4 (m, vinyl H), 5.77 (d, J = 12Hz, 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-benzyloxyphenyl) -2-methylpropionaldehyde (40.0 g, 0.157 Mol) and heptyltriphenylphosphonium bromide (6O ₅ O g, 0.138 mol)

R _f : 0.72 (silica gel), 33 % ithercyclohexane).

207 79 9

1-Benzyloxy-3- (1 _V 1-dimethyl-2 ~ decenyl) benzene as an oil (43 g,

78 %) of 2- (3-benzyloxy-3-phenyl) -2-methylsilylpropionaldehyde (40.0 g, 0.157 mol) and octyltriphenylphosphonium bromide (81.0 g, 0.178 mol)

IR: (CHCl ₃ ) 1621 and 1600 cm ^-1 .

MS: (m / e) 350 (M ⁺ ), 335, 308, 281, 263, 251 and 91.

PMR: Vj ^ q ₁ 0.83 (m, terminal methyl), 1.37 (s, according to dimethyl), 3.503 (s, benzylimethylene), 5.23 (dt, J = 11 and Hz, vinyl -H), 5.54 (bd, J = 11Hz, vinyl H) and 6.65-7.55 (m, ArH).

_i 1 _i -Be nzyloxy-3- (1 <1-dimethyl-2-undecyl) benzene as an oil (36 g,

63 %) of 2- (3-benzyloxyphenyl) -2-methylpropionaldehyde (.4-0.0 g, 0.157 mol) and Konyltriphenylphosphoniumbromid (81.1 g, 0.173 mol).

IR: (CHCl ₃ ) 1613 and 1592 cm ^-1 .

MS: (m / e) 364 (M ⁺ ), 349, 321, 295, 273, 251 and 91.

PMR: cTJE ^ l 0.87 (m, methylene), 1.38 (s, according to dimethyl), ^ 5.03 (s, benzylimethylene), 5.25 (dt, J = 12 and 6 Hz, vinyl H), 5.65 (bd, J = 12Hz, vinyl H) and 6.65-7.6 (in, ArH).

Presentation D

3- (1,1-methylthylheptyl) 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-charcoal in 100 ml of ethanol for 1 hour hydrogenated in a Parr apparatus at a hydrogen pressure of 50 psi, after a reaction time of 1 hour and 2 hours, another 7.5 g portions were added 10 % palladium on carbon 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.

PMR: ™C1 ^{0 85 85 (bt} * t ^e i ia & les methyl), 1 -1.9 (m, methylenes), 1.29 ³ (s, according to dimethyl), 4.98 (s, phenol H) and 6.6-7.4 (m, ArH).

IR: (CHCl ₃ ) 3571, 3311 and 1592 cm " ^1. ' MS: m / e 220 (M ⁺ ), 205 and 135 «.

In the same way were prepared: 3 -, (1? -1 -Dimethyloctyl) phenol in a yield of 82 % (7.8 g) of 13.0 g (0.0406 mol) of 1-benzyloxy- »3- (1 $ 1 -dimethyl-oct-2-enyl) benzene * It was obtained as an oil having the following characteristics:

PMR: (Ζ ™ ^ _χ Oj85 (m, terminal methyl), 1.27 Cs, gem dimethyl.), ³ 5.25 (bs, OH) and 6.6 to 7.4 (m, ArH). IR: (CHCl ₃ ) 3571, 3279, 1563, and 1527 cm ^-1 ··· MS: m / e 234 (M ⁺ ), 219, 191, 178, 164, 149, 135, and 121.

3- (1,1-dimethylpropyl) phenol as oil C "M, 7 g" (78 %) of 1-benzyloxy-3- (1,1-dimethyl-2-propenyl) benzene (23.0 g, 0.0912 mol).

PMR: (f ^ ₁ 0.67 (t, J = 7 Hz, terminal methyl), 1.23 Cs,

gem. Dimethyl), _1S 58 (q, J = 7Hz, methylene), 6.03 (s, OH) and

6.6-7.4 (m, ArH).

IR: (CHCl ₃ ) 3534, 3300, 1613 and 1587 cm ^-1 .

MS: m / e I64 (M ⁺ ), 149, 135 and 108?

3 -, (1,1-dimethylbutyl ) phenol as an oil (21.0 g, 84 %) of 1-benzyloxy-3-C 1,1-di-ethyl-2-butenyl) benzene (37.3 g, 0.140 mol ).

PMR: ^^ gx 0 ₉ 85 (m, terminal methyl), 1.18 (s, according to Di ³

^ gx ₉ y

methyl), ³ 5.42 (bs, OH) and 6.5-7.3 Cm, ArH).

"" ¹

5 "" ¹

y, IR: (CHCl ₀ ) 3623, 3448 and 1613 cm "MS: m / e 178 (M ⁺ ), 163, 135, 121 and 107 *

- ΑΧΟ -

3- (1 → 1- Dimethylpentyl) -phenol as an oil (16 g, 75 %) of 1-benzyloxy-3- (1,1-dimethyl-2-pentenyl) -benzene (31.0 g, 0.111 mol). IR: (CHCl ₃ ) .3636, 3390, 1634, 1623 and 1605 cm ^-1 MS: (m / e) 192 (M ⁺ ), 135 and 108.

PMR: ^ ¹ QVQ ₁ 0.82 (m, methyl), 1.26 (s, according to dimethyl) and 6.5-7.4 ³ (m, ArH).

3- (1,1-dimethylhexyl) phenol as an oil (18 g, 74 %) of 1-benzyl-oxy-3- (1,1-dimethyl-2-heen: enyl) benzene (35.0 g, 0.119 mol IR: (CHCl) 3650, 3390 and 1626 (wide) cm ^-1 . MS: (m / e) 206 (M +), 191, 177, 163, 149 and 135.

PMR: c / ₁ 0.80 (m, methyl), 1.22 (s, according to dimethyl) and 6.5-7.3 ³ (m, ArH).

3- (1,1-Di methylnonyl) phenol as an oil (20.6 g, 86 %) of 1-benzyl oxy-3- (1,1-dimethyl-2-nonenyl) benzene (34.5 g, 0.103 mol ). IR: (CHCl) 3636, 3378 and 1613 (wide) cm ^-1 . MS: (m / e) 248 (M ⁺ ), 233, 192, 178 and 135.

^ ₁ 0.86 (m, terminally methyl), 1.22 (s, according to _t- 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 (43.0g, 0.123

IR: (CHCl) 3636, 3333 and 1613 (wide) cm " ¹ .

MS: (m / e) 262 (M ⁺ ), 247, 206, 191, 178, 166, 155 and 135.

PMR: Cf ^ ₁ 0.88 (m, terminal methyl), 1.23 (s, dimethyl) and 6.5-7.4 (m, ArH).

3.7. (1 j , 1-Dirnethylundecyl.) Phenol as an oil (21 g, ₉ 77 %) of 1-benzyloxy-3- (1,1-dimethyl-2-undecenyl) benzene (36 g, 0.099 mol),

IR: (CHCl ₃ ) 3534, 3279 and 1597 cm ^-1 .

MS: (m / e) 276 (M ⁺ ), 261, 220, 184 and 135.

PMR: <? ^ ₁ 0.87 (m, terminal methyl), 1.22 (s, according to dimethyl), ³ 5.1 (broad, OH), and 6.5-7.3 (m, ArH).

-2 -me thyloc t

To a 0 ⁰ C-containing solution of 110 g (0.50 mol) of 2- (3-hydroxyphenyl) -2 ~ methyloctan in 200 ml of carbon tetrachloride was added dropwise a solution of 80 g (0.50 mol) of bromine in 90 ml of carbon tetrachloride (Reaction temperature - 30 ⁰ C 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: O ™ _χ 0.85 (bt, terminal methyl), 0.8-1.9 (m,

Methylene), ³ 1.28 (s _s according to dimethyl), 5.4 (bs, phenolic H), 6.78 (dd, J = 8 and 2 Hz, C-6-ArH), 7.02 (i.e. , J = 2 Hz,

C-2-ArH) and 7.37 (d, J = 8Hz, 0-5-ArH).

IR: (CHCl ₃ ) 3559, 3289 and 1585 cm ^-1 .

MSi m / e 300, 289 (M ⁺ ), 215, 213, 201, 199, 187 and 195.

In the same way were prepared:

2- (4-bromo-4-hydroxy- phenyl) -2-methylnonane in 82 % yield (8.5 g) as an oil from 7.8 g (0.033 mol) of 2- (3-hydroxy )

xyphenyl) ~ 2-methylnonane. <r

PMR: 0 ^ Q Q ₁ 0.86 (m, terminal methyl), 1.27 (. S, gem dimethyl), ³ 5.50 (bs, OH), 6.83 '(dd, = 8 and 2 J Hz, ArH), 7 _s 08 (d, J = 2 Hz, ArH) and 7.43 (d, J = 8 Ha, ArH). IR: (CHCl ₃ ) 3279, 1613 and 1587 cm ^-1 . MS: m / e 3H, 312 (M ⁺ ), 212, 210, 185 and 187.

-j [-hy ^ as an oil (12.7 g, 98

2- (3-hydroxyphenyl) -2-methylbutane (9.50 g, 0.0579 mol)

H, IR: cf ™ 1 ° ^'67 (* » ^J = 7 ^Hz > terminal methyl), 1.23 (s, according to dimethyl), 1.56 (q, J = T Hz, methylene), 5.2 (bs,

OH), 6.84 (dd, J = 8 Hz, ArH).

IR: (CHCl) 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-hydroxyphenyl) -2-methylpentane as an oil (29.9 g, 99 %) of 2- (3-hydroxyphenyl-2-methylpentane (21.0 g, 0.118 mol).

PRiRrO Q ^ Jq 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, ArIi). IR: (CHCl ₃ ) 3610, 3333, 1618 Lind 16OO cm ~ ¹ .

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

2- (4-Bromo-3-hydroxyphenyl) -2-methylhexane as an oil (22.8 g,

100 %) of 2- (3-hydroxyphenyl) -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

2- (4-Bromo-3-hydroxyphenyl) -2- methylheptari as an oil (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, 2.13, 187 and 185.

Piir: (a., Gem dimethyl) ^ ™ Q _X 0.87 _(s ra terminalea methyl), 1.30 - ³ 5.49 (bs, OH), 6.83 (dd, J = 8 and 2 Hz , ArH), 7.07 (d, J = 2 Hz, ArH) and 7.42 (d, J «8 Hz, ArH).

2 ~ (4 ~ broro ~ 3 ~ hydro: c ^ henyl) -2 ~ methyldecan ala oil (23.2g, 85 $) of 2- (3-hydroxyphenyl-2-methyldecax »(20.6g, 0, 0831

IR: (CHCl ₃₎ 3571, 3333 and 1661cm "^'1.

MS: (m / e) 328 and 326 (M ⁺ ), 313, 311, 215 and 213 ·

WR: <ff ^ ci ° »82 (m, terminal methyl), 1.30 (s, gem" dimethyl), 3.50.49 (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_> hy droxy ° phe nyl) -2- methylun ° decane as an oil (quantitative) of 2 ~ (3-hydroxyphenyl) -2 ~ inethylhendecan (21.0 g, 0.0802 mol)

IRi (CHCl ₃ ) 3571, 3333 and 1600 (wide) cm " ¹

MS: (m / e) 342 and 340 (M ⁺ ), 215, 213, 187 and 185.

PMR: ^ CPc ₁ 0.86 (m, terminal methyls), 1.22 (s, according to dimethyl), ³ 5j45 (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, ArH).

2- (4-bromo ^ 3-hydroxyphenyl) -2-methyldodecane as an oil (22.0 g, 81 %) of 2- (3-hydroxyphenyl) -2-methyldodecane (21.0 g,

0.0761 mol).

IR: (CHCl ₃ ) 3597, 3333, 1613 and 1592 cm ^-1 .

MS: (m / e) 356 and 354 (M ⁺ ), 340, 338, 215 and 213.

PMR: cTqpc! 0.92 (m, terminal methyl), 1.29 (s, gem. Dimethyl), ³ 5.47 (bs, OH), 6.81 (dd, J "," 8 and 2 Hz, ArH), 7, 06 (d, J = 2 Hz, ArH) and 7.41 (d ₅ J = 8 Hz, ArH),

    ·· Presentation P

2- (3-benzyl-lo: xy-4-bromophenyl) -2-inethyloctan To a -18 ⁰ C having slurry of 23.0 g (0.575 mole) of potassium hydride in 400 ml Ν, Ν-dimethylformamide wurde'über a period of 45 minutes a solution of 150 g (0.5 mol) of 2- (4-bromo-3-hydro 2cyphenyl) -2-methyloctan in 400 ml of H, H-dimethylformamide given (reaction temperature ^ -15 ⁰ C) ₆ The reaction mixture was more Stirred for 15 minutes, whereupon a solution of 98.3 g (0.575 mol) of benzyl bromide in 200 ml of N ₁ H-.

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 washed six times

Extracted 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.

PMR: cT ™ ^ 0.85 (bt, terminal methyl), 0.8 to 2.0 (m, methylenes), 3 1.22 (s, gem dimethyl.), 5.17 (s, benzylmethylene) and 6 , 7 - 7.6 (two multiplets, ArH and PhH). IR: (CH 2 Cl 2) 1592 and 1575 cm ^-1

MS: m / e 390, 388 (M ⁺ ), 375, 373, 354, 352, 305, 303 and 91.

2- (3 -Benzyloxy-4-bromophenyl-2-methylnonane was isolated in 95% yield (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.

HER: '</ "; 5K, 0.87 (terminal methyl), 1.23 (s, according to dimethyl), * 5.18 (s, benzylethermethylene), 6.8 (dd, J = 8 and 2 Ha , ArH), 6.97 (d, J = 2 Hz, ArH) and 7.43 (m, ArH and PhH) ♦

- / IiS

207 799

IR: (CHCl ₃ ) 1600 and 1575 cm ^-1 .

MS: m / e 404, 402 (M ⁺ ), 3Ö5, 303, 91 j

2 - (3-benzyl oxy-47.brpmph.enyl) -2-methylhydrogen (46.5 g, 88 %) of 2 "- (4-bromo-3-hydroxy-phenyl-2-methylpropane (38.0 g, 0.166

Melting point: 52 to 54 ^° C (from pentane).

IMR: ^ö cpci ¹ * ²⁵ ^ ^s > + - "butyl", 5.18 (a, benzylethermethylene) 6.7 - 7.0 ^3. (m, two ArH) and 7.2 - 7.6 (m, an ArH and PM) IR: (CHCl ₃ ) 1600 and 1585 cm ^-1

MS: m / e 320, 318 (Li ⁺ ), 305, 303, 239 and 223?

_i 2 ~ (3-benzyloxy-4 ~ bromophenyl) -2 ~ methylbut _{to a]} _ _s Qi (24.9 g, 99 fo) of 2- (4-bromo-3-hydroxyphenyl) -2-metliylbutan (17 , 3 g, 0.0777 mol).

IR: (CHCl ₃ ) 1600 and 1585 cm ^-1 .

MS: m / e 334, 332 (IiI ⁺ ), 319, 317, 309, 303, 253, 223 and 91.

2 ~ (3-benzyloxy-4-bromophenyl) -2-ethylpenta, n as an oil (34.3 g, 99 %) of 2- (4-bromo-3-hydroxyphenyl) -2-methylpentane (25.7 g, 0.100 mol). ·

PMR: d '^ q ₁ 0.80 (m, terminal methyl), 1.23 (s, according to dimethyl), 3 5.12 ( _Sj benzylethermethylene), 6.6-6.9 (m, zvsei ArH) and 7.1-7.5 (m, ArH and PhH). IR: (CHCl) 1610 and 1595 cm ^-1

MSj m / e 348, 346 (M ⁺ ), 333, 331, 305, 303 and 91.

2- (3-Benzyloxy-4-brono-phenyl) -2-methylhexane as an oil (30 g, 98 %) of 2- (4-brcaa-3-hydroxyphenyl) -2-methylhexane) 22.7 g, 0.0831 mol )

IR: (CHCIo) 1605 and 1592 cm "" ¹ ·

- 426 -

MS: (m / e) 363 and 361 (M ⁺ ), 305 and 303.

PMR: O ™ S · _Oil Q _{(m> term} i _nalea methyl), 1.18, 5.12 ^ (3, benzylmethylene), 6.65 to 6.9 (m, ArH) (a, gem dimethyl). and 7.15 - 7.6 (m, ArH and Ph).

2- (3-Benzyloxy ) -4-bromophenyl) -2-methylheptane as an oil (quantitative) of 2- (4-bromo-3-hydroxy-phenyl) -2-methylheptane (23.0 g, 0.0806 mol).

IR: (CHCl ₃ ) 1600 and 1582 cm ^-1 . MS: (m / e) 376 and 374 (M ⁺ ), 305, 303, 215 and 213.

PMR: cf ^ q ₁ 0.80 (m, terminalea methyl), 1.19, 5.12 ³ (s, benzylmethylene), 6.65 to 6.95 (m, ArH), (. A gem dimethyl). 7.15 7.6 (M, ARH and Ph).

2- (3- benzyloxy- 4-bromophenyl) -2-methyldecane as an oil (quantitative) of 2- (4-bromo-3-hydroxyphenyl) -2-methyldecane (23.2 g, 0.0712

IR: (CHCl) 1600 and 1585 cm ^-1 . MS: (m / e) 418 and 416 (M ⁺ ), 305, 303, 215 and 213.

PMR: rf ^ DQ ₁ 0.91 <m, terminalea methyl), 1.26 (s, according to dimethyl), 3 5 _j19 ( _s> benzylmethylene), 6.7-7.0 (m, ArH) and 7 , 25-7.65 (m, ArH and Ph).

2- (3-Benzyloxy-4- bromophenyl ) -2-methylundecane as an oil (40.0 g, 82 %) of 2- (4-bromo-3-hydroxyphenyl) -2-methyl-hexane (27.3 g,

0.113 moles).

IR: (CHCl ₃ ) 1605 and 1587 cm ^-1 .

MS: (m / e) 432 and 430 (M ⁺ ), 305, 303, 215 and 213.

PMR: ^ ™ _X q 0.90 (m, terminalea methyl), 1.24, 5.18 ³ (s, Benzylmethan), 6.7 to 7.0 (m, ArH) and (s, gem dimethyl). 7.2 7.6 (m, ArH and Ph).

2- (3-Benzyl oxy-4-bromophenyl) -2-meth yldodecane as an oil (27.5 g, 100%) of 2- (4-bromo-3-hydroxyphenyl) -2-ethyldodecane (22.0 g,

0.0620 MoI).

IR: (CHCl ₃ ), 1605 and 1592 cm ^-1 .

MS: (m / e) 446 and 444 (M ⁺ ), 305 and 303.

PMRs ^ CDQ2 ° ^β 6 ( ^m * terminal methyl) _s 1,21 (s, according to dimethyl), 3 5,13 (s, benzylmethylene), 6,7-6,95 (m, ArH) and 7, 2 - 7.55 (m, ArH and Ph).

The compounds listed below are prepared from appropriate reactants according to the procedures given for C-P representations:

Z-W

C (CH ₃ ) ₂ (CH ₂ ) ₄ ^C 6 ^H 5 C (CH ₃ J ₂ (OHJ ₄ 4-pyridyl 3 2 2 3 2-pyridyl CC CH_) _ (CH ₀ ) -t 0 yes ά IU ^C 6 ^H 5 CH (CH ₃ ) (CH ₂ ) ₂ ^C 6 ^H 5 CH (O ₂ H ₅ ) (CHg) ₉ 4-ClC ₆ H ₄ CH (C Hc) (CH ₉ ): 4-PC ₆ H ₄ H (CHg) ₁₁ H (CH ₂ ) ₁₃ H < ^CH 2> 4- ^C 6 ^H 5 (CH) ₈ H

- 42. "- 207

, Preparation G _i 3 Benzyl loxy- 4-bromophenol

To a O ⁰ C-containing slurry of 1.7 g (42.5 mmol) of potassium hydride in 35 ml of H, N-dimethylformamide was slowly added a solution of 7.22 g (38.2 mmol) of 4-bromoresorcinol. The resulting mixture was stirred for 30 minutes and then 4 _{S of} 54 ml (38.2 mmol) of benzylbromide was added slowly. The reaction mixture vmrde continued for 3 hours at 0 ⁰ C and stirred subsequently added to 200 ml of cold .Water and 200 ml ether. The ethereal extract was washed twice with 200 ml portions of water, dried over magnesium sulfate and evaporated to an oil. The crude oil was purified by column chromatography from 400 g of silica gel eluting with 25 % A'the rP to give (in order of elution) 2.2 g (16 %) of .2,4-dibenzyloxybromobenzene. 0.21 g (2 %) of 5-benzyloxy-2-bromophenol and 3 g of 52 g (33 %) of 3-benzyloxy-4-bromophenol.

5-Benzylo: gy-2-bromophenol:

PMR: ⁰ ^ ₁ 4.98 (s, benzyl ether), 5.46 (bs, OH), 6.40 (dd,

J = 8 and 3 2 Hz, ArH), 6.60 (d, J = 2 Hz, ArH), 7.17 (d,

J = 8 Hz ₉ ArH) and 7.33 (s, PhH).

IR: (CHCl ₃ ) 3521, 3221, 1610 and 1600 cm ^-1 .

MS: m / e 280 and 278 (M ⁺ ), 189, 187 and 91. · 3- benzyloxy-4 - bromophenol :

PMR: ^^ 2 5.00 (s, benzylethermethylene), 5.33 (bs, OH),

6.21, (dd, ³ J = S and 2 Hz, ArH), 6.38 (d, J = 2 Hz, ArH)

and 7.30 (m, ArH and PhH). ,

IR: (CHCl ₃₎ 3546, 3257, 1603 and 1585 cm "^'1.

MS: m / e 280, 278 - (M ⁺ ) and 91.

Paragraph H

2-Benzyloxy-4-p-2- (5-phenylpentyloxy ) -bromobenzene A mixture of 3.50 g (12.5 mmol) of 3-benzyloxy-4-bromophenol, 3j48 g (14.4 mmol) 2- (5 -Phenylpentyl) methanesulfonate and 5.17 g (37.5 mmol) of potassium carbonate in 20 ml -wasserfreiem 1? 1T-dimethylformamide was 6 hours maintained at 85 ⁰ C, "Ea was then cooled and added to 200 ml of water and 200 ml Ether. The organic extract was washed twice with 150 ml portions of water, dried over magnesium sulfate and evaporated to an oil. The oil was purified by column chromatography on 400 g of silica gel eluting with a 2: 1 mixture of pentane and methylene chloride to give 4.39 g (82 %) of the intended product as an oil.

PMR: cfSSn 1.21 (d, J = 6 Hz, side chain methyl), 1.7 (m,

XAj J- -j

Seitenketterimethylene), 2.60 (m, side chain benzylmethylene), 4j25 (m, side chain methine), 5.00 (s, benzylethermethylene), 6.22 (dd, J = 8 and 2 Hz, C-5-ArH), 6.39 (d, J = 2 Hz, C-3 ~ ArH)

and 7.30 (m, PhH and C-6-ArH).

IR: (CHGl ₃₎ 1 ₅ 87 cm "^'1.

MS: 426, 424 (M * ⁴ "), 280, 278 and 91.

The following compounds are similarly prepared from the appropriate mesylate CH.SO.sub.i -Z-W.

0- (alk ₂ ) -W

CCHg) ₄

(CHg) ₈

(CHg) ₁₀

CH (CH ₃ ) (CHg) ₈

CH (CH ₃₎ CHg C (CH ₃₎ g (CHg) ₃ CH ₂ CH (CH ₃₎ CHg CH (CH ₃₎ (CHg) ₁₀

C (CH ₃₎ g (CHg) ₇

(CHg) ₁₃

CH (CH ₃₎ (CHG) ₆ C (CH ₃₎ g (CHg) ₁₀ (CHg) ₁₂

CH (CGH ₅₎ (CHg) ₃ C (CH _{3) 6} g (CHG) (CH ₂₎ gC (CH _{3) 2} (CH ₂₎ g

CH _(CH3) (CHg) ₃

(CH ₂ ) ₂

CH _(CH3) (CHg) ₃

(CHg) ₁₀

2 ⁿ 5 ·

4-FC ₆ H ₄ ^C 6 ^H 5 4-ClC ₆ H ₄ Hh 4-FC ₆ H ₄ Hh ^C 6 ^H 5 · H

H H H

^C 6 ^H 5 .4-FC ₆ H ₄ 4-FC ₆ H ₄ ^C 6 ^H 5 4-ClC ₆ H ₄

H H

^C 6 ^H 5 H

4-Pyridyl 4-Pyridyl 2-Pyridyl 3-Pyridyl 2-Pyridyl 4-Pyridyl

Presentation I

j-Bro m-2 ₁ 4 ~ di benzylqx ybenzol

A mixture of 75.0 g (0.397 mol) of 4-broaresorcinol, 95.1 ml (0.80 mol) of benzyl bromide and 331 g (2.4 mol) of anhydrous potassium carbonate in 400 ml of Ν, Ν-dimethylformamide was added for 12 hours at 25 ⁰ C and 4 hours at 85 ⁰ C stirred. The reaction mixture was cooled and added to 1 liter of Sis / 200 ml of pentane / 100 ml of ether. The organic phase was washed with three 550 ml portions of water, dried over magnesium sulfate and evaporated to an oil. The oil was rapidly chromatographed on 400 g of silica gel eluted with 20 % ether-pentane to yield 80 g of oil. The chromatographed oil was recrystallized at 0 ⁰ C from pentane to give 4510 g (30%) of the title compound having a melting point of 37-38 ⁰ C.

PMR: ^ ^ 5.0 (s, C-4-benzylethermethylene), 5.08 (s, C-2-benzyl ether ^ ethylene), 6.45 (dd, J = 8 and 2 Hz, C-5H), 6.63 (d, J = 2 Hz, C-3H), 7.2-7.6 (m, PhH and ArH), IR: (CHOl ₃ ) 1605 and 1590 cm ^-1

MS: m / e 370 (M ⁺ ), 368 and 91.

Analysis: Calculated for C ₂₀ H ₁₇ BrO ₂ : C, 65.03; H, 4.64; Br, 21.65

Found: C, 64.95; H, 4.55; Br, 21:48

Presentation J

2- (3-Methoxyphenyl ) -5-phenylpentane

A solution of 1-bromopropylbenzene (51 _S, 7 g) in ether (234 mL) is added dropwise over 2 hours to a refluxing mixture of magnesium (7.32 g) in ether (78 mL). The reaction mixture is refluxed for an additional 30 minutes, then a solution of 3-methoxyacetophenone (41.6 g) in ether (78 ml) is added dropwise and the mixture is refluxed for 1 1/2 hours. The reaction mixture is quenched by the addition of saturated ammonium chloride, the ether layer is separated and the aqueous phase is extracted with ether (3 x 200 ml).

The combined ether extracts are concentrated over magnesium sulphate and concentrated under vacuum to an oil. The oil is dissolved in one of ethanol (300 ml), concentrated hydrochloric acid (2 ml) and 5 % palladium on carbon (5 g). hydrogenated existing mixture. The catalyst is filtered off and the ethanol is removed under vacuum. The residue is distilled under vacuum to yield the title product.

Presentation K

2- (3-hydroxyphenyl) -5-phenylpentane

A mixture of 2- (3-Methoxyphenyl) -5-phenylpentane (18.4 g) and pyridine hydrochloride (94 g) is kept under nitrogen for 2 hours with vigorous stirring to 190 ⁰ C. The reaction mixture is cooled, dissolved in 6N hydrochloric acid (200 ml) and diluted to 600 ml with water. The aqueous solution is extracted with ethyl acetate (4 × 100 ml), the ethyl acetate extracts are dried over sodium sulfate and concentrated under vacuum to yield the crude product. The product is purified by silica gel chromatography »

The following compounds are prepared from the appropriate reactant by the method of Figure J and the procedure set forth above:

Z-W

-435 207

Z J [

CH (CH ₃ ) (CH-) ₂ CH (C ₀ H ₁ - "

H H H

By bromination of the above compounds according to the procedure of Preparation E, the corresponding 4-bromo derivatives are obtained, for. B. 2- (4-bromo-3-hydroxyphenyl) -5-phenylpentane.

Presentation L

Ethyl 3- (3-ben- zyloxyphenyl ) crotonate

. (Wittig reaction)

A mixture of 3-benzyloxyacetophenone (29 »4 g» 0.13 mol) and carboxymethylenetriphenylphosphorane (90.5 g> 0.26 mol) is kept at 170 ^° C. for 4 hours under a nitrogen atmosphere. The clear melt is cooled to room temperature, triturated with ether and the precipitate of triphenylphosphine oxide is removed by filtration. The filtrate is concentrated under vacuum to an oily residue which is chromatographed over silica gel (1500 g) eluting with benzene: hexane solutions with increasing benzene concentration starting with 40:60 and stopping with 100 % benzene. Concentration of the appropriate fractions gives the product as an oily residue.

Darat el lump; M

3- (3-benzyloxyphenyl) butyl tosylate

A solution of ethyl 3- (3-benzyloxyphenyl) crotonate (17.8 g, 60 mmol) in ether (250 mL) is added to a mixture of lithium aluminum hydride (3i42 g, 90 mmol) and ether (250 mL), aluminum chloride (0.18 g, 1.35 mmol) is added and the mixture is refluxed for 12 hours and then cooled. Then, water (3 _t, 4 ml), sodium hydroxide (3.4 ml, of 6H) and water (10 ml) are successively added to the reaction mixture. The precipitated inorganic salts are filtered off and the filtrate is then concentrated under vacuum to yield the 3- (3-benzyloxyphenyl) butanol in the form of an oil.

Tosyl chloride (11.1 g, 58.1 mmol) is added to a solution of 3- (3-benzyloxyphenyl) -1 ~ butanol (14.5 g, 57 mmol) in pyridine (90 ml) at -45 ⁰ C. The reaction mixture is kept for 18 hours at -35 ⁰ C and then diluted with cold 2U hydrochloric acid (1500 ml) and with ether (5 x 200 mL). The combined extracts are washed with saturated sodium chloride solution (4 x 250 ml) and then dried (NapSO . ). Concentration of the dried extract gives the product as an oil.

Presentation IT

3- (3- benzyloxy phenyl) -1-phenoxybutane

A solution of phenol (4.56 g, 48.6 ml viol) in dimethylformamide (40 ml) is added under a nitrogen atmosphere to a 50% suspension of (previously washed with pentane) sodium hydride (2.32 g, 48.6 mmol). in dimethylformamide (70 ml) at 60 ^° C. The reaction mixture is stirred for 1 hour at 60 to 70 ⁰ C and a solution of 3- (3-benzyloxyphenyl) butyl tosylate (18.9 g, 46 mmol) in Dirnethyiformamid (80 ml) is added. The reaction mixture is 1/2 hour

Stirred at 80 ⁰ C, then cooled to room temperature, diluted with cold water (2500 ml) and extracted with ether (4 x 400 ml) The combined extracts are washed successively with cold CH hydrochloric acid (2 χ 360 ml) and saturated sodium chloride solution (3 χ 300 ml) and then dried (Ua ₂ SO _4). Durch'Entfernen of the solvent under reduced pressure, the product is recovered in the form of an oil. the oily residue v? ird dissolved in benzene and · by Silleagel (TOO g filtered by evaporation of the filtrate under reduced pressure, the product is obtained in the form of an oil.

By repeating L to U but using the 3-benzyloxy derivatives of benzaldehyde, acetophenone or propiophenone, the appropriate carbethoxy (or carbmethoxy) alkylidene triphenylphosphorane and the appropriate alcohol or phenol, the following compounds are obtained:

(all,) - (HaIk ₂ ) _n -

Calcium ₁ ) η CaIk ₂ ) W

(CHg) ₃ 1 (CH ₂ ) ₃ H (CH ₂ ) " 1 (CHg) ₅ H (CHg) ₅ 1 (CHg) ₈ H (CHg) ₆ 1 (CHg) ₇ H (CHg) ₃ 1 (CH ₂ ) ₇ H f f TJ \ 1 (CHg) ₁₀ H (CH _o ) ₁₀ 1 (CHg) ₂ H C (CH) _o (CR ₂ ) 1 (CH ₂ ) ₄ H (CH ₂ ) - ": 1 CH ₂ ^C 6 ^H 5

, £ 07,799

(alk J

(CH ₂ ) ₆ (CH ₂ ) ₆

(CHg) ₆

CH (CH ₃ ) (CH ₂ ) ₂ CH (CH J (CH ₂ ) ₃ CH (CH J (CHg) ₆ (CH K

(CHg) ₃

CH (CH ₃ ) (CH ₂ ) ₂ CH (C ₂ H ₅ ) (CH ₂ ) ₂

O O O O O O O O 1 1 1 1 1

(alk ₂ )

CH

CH (CH ₃ )

CH (CH ₃ )

^C 6 ^H 5 H

4-ClC ₆ H ₄

4-PC ₆ H ₄

^C 6 ^H 5

^C 6 ^H 5 H

4-Pyridyl 3-Pyridyl 2-Pyridyl 4-Pyridyl 2-Pyridyl 4-Pyridyl 4-Pyridyl

By debenzation of the products obtained by the method of Preparation E, the corresponding 2-bromo-5-t (alk-j) -O- (alk ₂ ) _n -V / 1 phenolbenzyläther which are brominated by the procedure of Preparation E. , won. Benzylation of the bromophenols so produced by the procedure of Example F gives the benzyl ether of 2-bromo-5- [KaIk ₁ ) -O- (alk ₂ ) _m -W] phenols.

Presentation O

4- (3-hydroxyphenyl) -1- (4-pyridyl) pentan

A mixture of 3- (3-methoxy-phenyl) -butyltriphenyl-phosphonium bromide (17 * 5 g, 35.4 mmol) in dimethylsulfoxide (50 ml) is added to 4-pyridinecarbosaldehyde (3.79 g, 35.4 mmol) in tetrahydrofuran (40 ml). The resulting mixture is then added dropwise to a slurry of 50% sodium

hydride (1.87 g, 39 mmol) in tetrahydrofuran (20 ml) under a nitrogen atmosphere at 0 to 5 ⁰ C and then concentrated under reduced pressure. The concentrate is diluted with water (200 ml) and then acidified with 6 H HCl. The aqueous satire solution is extracted with benzene (4 χ 50 ml). It is then basified and extracted with benzene (3 × 50 ml). Evaporation of the combined extracts after drying (MgSO 4) gives 4- (3-methoxyphenyl) -1- (4-pyridyl) -1-pentene as a Oil won.

Catalytic hydrogenation of the thus-produced pentene derivative in ethanol at 45 psi in the presence of Pd / C (1 g, 10%) and concentrated HCl (1 ml) gives the title product.

By using a mixture of the compound (25 mmol) and pyridine hydrochloride (35 g) is kept under a nitrogen atmosphere for 8 hours at 210 ⁰ C. The pentane derivative thus generated "is demethylated. The hot mixture is poured into water (40 ml) and the resulting solution is basified with 6U sodium hydroxide, water and pyridine are removed by distillation under vacuum, ethanol (50 ml) is added to the residue and the precipitated inorganic salts are filtered off, the filtrate is concentrated in vacuo and the residue is on silica gel using 5 $ 'ethanol / benzene (4 liters), 10 % ethanol / benzene (1 liter), 13 % ethanol / benzoil (1 liter) and 16 % ethanol / benzene (5 liters) as eluent The product is isolated by concentration of suitable eluate fractions. »

The 3- (3-methoxyphenyl) butyl triphenylpliosphonium bromide is isolated by refluxing a mixture of

1-Bromo-3- (3-methoxyphenyl) butane (78.5 mmol) and triphenylphosphine (78.5 mmol) in xylene (60 ml). The reaction mixture is then cooled to room temperature and filtered. The filter cake is washed with ether and the product is dried in a vacuum desiccator.

By repeating this procedure but using the appropriate bromo (3-methoxyphenyl) alkane and the appropriate aldehyde or ketone, the following compounds are recovered.

OH

Z-W

₂₄

CH (CH ₃₎ CH (GH ₃₎ CH ₂ CH (CH ₃₎ CH (CH ₃₎ CH ₂

₃₃

CH (C ₂ H ₅ ) (CH ₂ ) (CH ₂ ) ₁₀

2-pyridyl 4-pyridyl 3- * pyridyl 4-pyridyl 4-pyridyl 4-pyridyl

Brominating the above compounds by the method of Preparation E yields the corresponding 2-bromo-5- (Z-W) -phenols.

Presentation P

3-methoxy-o <-mine-thyl oxide. ,

To a solution of Dimethylsulfoxoniummethylid (69> 4 mmol) in dimethyl sulfoxide (65 ml) is solid at room temperature

07 79 9

Added 3-dimethoxyacetophenone (8.33 g, 55.5 mmol). The reaction mixture is stirred for 1 hour at 25 ⁰ C, 1/2 hour at 50 ⁰ C and then cooled. The mixture is diluted with water (50 ml) and added to a mixture of ice-water (200 ml), ether (250 ml) and low-boiling petroleum ether (25 ml). The organic extract is washed twice with water (250 ml), dried (MgSO 4) and evaporated to an oil which is fractionally distilled »

Presentation Q

2- (3 "Me thoxyphenyl) -2-hydrox ypropyl" -2 ~ phenyläthyläther A mixture of dry 2-phenylethanol (30 ml, 250 mmol) and sodium metal (690 mg, 30 mmol) is kept at 110 ⁰ C for 30 minutes , The resulting 1 M solution of sodium 2-phenyläthoxid is cooled to 60 ⁰ C, 3-methoxy-ck -methylstyroloxid (1.69 g> 10.3 mlvlol) is added and the reaction mixture is for 15 hours at 60 ⁰ G held. The reaction mixture is cooled and added to a mixture of ether and water. The ether extract is dried over magnesium sulfate and evaporated. Excess 2-phenylethanol is removed by vacuum distillation (boiling point about 65 ^'0 C, 0.1 mm). The residue is purified by column chromatography on silica gel 60 (300 g) eluting in 15 ml portions with 60 % ither-pentane.

Representation R

To a 0 ⁰ C-containing solution of 2 ~ (3-methoxyphenyl) -2-hydroxypropyl-2-phenylethyl ether (498 mg, 1.74 mmol) in pyridine (2 ml) is added dropwise phosphorus oxychloride (477 til, 5 »22 mmol). where * The reaction mixture was allowed to warm to 20 ⁰ O over the course of 1 1/2 hours. It is then stirred for 1 1/2 hours at 20 ⁰ C and then added to ether (150 ml) and 15% sodium carbonate (100 ^: ml). The organic phase

- AH-O ~

is separated and washed with 15% sodium carbonate (3 × 50 ml), dried over magnesium sulfate and evaporated to an oil. The oil is dissolved in absolute ethanol (15 ml), 10 % palladium on carbon (100 mg) is added and the mixture is stirred under a hydrogen atmosphere. When hydrogen uptake stops, the reaction mixture is filtered through diatomaceous earth and the filtrate is evaporated to an oil. The oil is purified by preparative thin layer chromatography on silica gel plates eluting twice with 6: 1 pentane: ether to give the title compound.

Presentation S

2- ( 3-Hydroxyphenyl ) propyl-2-phenylethyl ether A mixture of 2- (3-hydroxyphenyl) propyl-2-phenylethyl ether (176 mg, 0.65 mmol), pyridine (0.4 mL, 4.96 mmol) and dry pyridine hydrochloride (4 g "34.5 mmol) is maintained at 190 ⁰ C for 6 hours. The reaction mixture is cooled and added to a mixture consisting of water (100 ml) and ether (150 ml). The ether extract is washed once with water (50 ml) and dried over magnesium sulfate together with an external ethereal extract (50 ml) of the aqueous phase and evaporated to an oil. The oil is purified by preparative thin layer chromatography and silica gel plates eluting six times with 30 % ether-pentane to give the title product.

The following compounds are prepared from suitable alkanols by the methods of Preparations Q and R:

(alk ₂ ) W

) ₇ - H

- (CH ₂ ) ₆ - C ₆ H ₅

(CH) ₅ - H

g ₅

-CH (CH ₃₎ CH ₂ H

-CH (CH ₃₎ (CHG) ₅ H

₆₄ 4-pyridyl 4-ClC ₆ H ₄

) ₃ - H

HHH -CH ₂ - C ₆ H ₅

To a -78 ⁰ C-containing solution of Diphenylsulfoniumäthylid (1.0 mol) in tetrahydrofuran (1 liter) is slowly added 3-Methoxybenzylaldehyd (1.0 mol). The reaction mixture vjird for 3 hours at -78 ⁰ C and then stirred to warm to room temperature allowed to stand. It is then added to ether water and the ether phase is separated. The

Ether phase is washed with water, dried (MgSO4) and evaporated. By fractional distillation of the residue, the title product is recovered.

Parteilung U

3 _i -. _(I ß-Hyaroxyphe n yl) -2-propylbutylä'ther

To a solution of sodium butoxide in butanol (0.5 liter of 1M) is added 3-methoxy-β-methylstyrene oxide (6.33 mol). The mixture is held at 70 ^° C. for 18 hours, then cooled and added to a mixture consisting of ether and water. The ether solution is separated, dried (MgSO.) And evaporated to give the crude product 2- (3-methoxyphenyl) -3-hydroxy-2-propylbutyläther · It vjird. purified by column chromatography on silica gel using ether-pentane elution.

Using the method of representation R, the title product is produced.

Similarly, the following compounds are prepared from the appropriate alcohols:

OH CHo i ³ 0- (alk ₂ ) ~ W Q CH ^ / \ W > < CH ₂ H (alk ₂ ) H (CH ₂ ) ₂ ^C 6 ^H 5 (CH ₂ ) ₇ 4-PC ₆ H ₄ (CH ₂ ) ₃ 4 ~ pyridyl (CH ₂ ) (CH ₂ ) ₂

207 79

(alk _o ). W

CH (GH ₃₎ (GE _{2) 2} H

CH (C ₂ H ₅ ) (OH ₂ ) ₃ H

CH (CH ₃ ) CH ₂ -C

CH ₂ H

(CH ₂ ) ₂ 4

Presentation V

I ^ bromine-3 ·· (ßrniethpxyphenyl) butane

A solution of phosphorus tribromide (5 »7 mL, 0.06 mol) in ether (30 mL) is added to a solution of 3- (3-methoxyphenyl) -1-butanol (30.0 g, 0.143 mol) in ether (20 ml) at a temperature from -5 to -10 ⁰ C, .and the reaction mixture is C 2 1/2 hours, stirred · at.-5 to -10 ⁰ It is then warmed to room temperature and further stirred for 30 minutes. The mixture is poured onto ice (200 g) and the resulting mixture is extracted with ether (3 x 50 ml). The combined extracts are washed with 5% sodium hydroxide solution (3 × 50 ml), saturated sodium chloride solution (1 × 50 ml) and dried (Na ₂ SO.). By removing the ether and vacuum distillation of the residue, the title product is recovered.

The following compounds are prepared from 3-methoxybenzaldehyde, 3-methoxyacetophenone and 3-methoxy-propionophenone and the appropriate carbethoxyalkylidene-triphenylphosphorane according to the procedures of Preparations L, M and the above presentation. »

OCH.

Z-Br

₂₅ CH (CH ₃ ) CH ₂ CH (CH) (

, Illustration W

Q-benzyloxy) benzyl oxypropane

Sodium (0.2 mol) is dissolved in n-propyl alcohol (1.0 mol) and the reaction mixture is then cooled in an ice bath. Subsequently, 0.2 mol of 3-benzyloxybenzyl chloride are added over the course of 1/2 hour with continuous stirring. * The ice bath is removed and the temperature is slowly increased to the reflux temperature. After refluxing for 4 hours, the excess alcohol is removed by distillation under reduced pressure. The residue is treated with water to dissolve the salt present and then extracted with diethyl ether. The extract is washed with water, dried (MgSO 4) and evaporated to give the title product.

In cases where the alcohol reactant is not readily available or is a solid at normal temperatures, a modification of this procedure is employed. The appropriate alcohol is dissolved in acetone and heated with the halide reactant in the presence of powdered potassium carbonate for 6 to 8 hours. The reaction mixture is then cooled, water is added and the ether recovered as described above.

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

O. 0

CH ₂ -O-CaCl ₂ ) .- W

(alk ₂ )

CCHg) ₂ H - ^C 6 ^H 5 (CHg) ₄ H -. 4-pyridyl (CHg) ₁₂ H CH (CHo) (CH ₉ ) ρ • j CL c ~ ^C 6 ^H 5 (CH ₂ ) ^C 6 ^H 5 CH ₂ ^C 6 ^H 5 CH (CH ₃ ) CH ₂ H (CH ₂ ) ₅ 4-FC ₆ H ₄ (CH ₂ ) ₂ CH (CH ₃ ) ° 6 ^H 5 CHpCH (CpHp-) CHp C- CS Cm H

Debenzylation of the products obtained by the method of Preparation E gives the corresponding 2-bromo-5- (C 1-10) _1- O- (alkg) _n -W] phenolbenzyl ethers which are brominated by the method of Preparation B * Benzylation of bromophenols produced in this manner by the procedure of Example ¹ gives the bensyl ether of k ₁ ) -O- (alk ₂ ) _a -w] plien.ole.

Pars division, X _-111 6- (3-butenyl) -3-etho3: v-'2-cyanohexene n- "1-one

A solution of 25 g (0.178 mol) of 3 ~ ethoxy-2-cyclohexen-1-one in 25 ml of tetrahydrofuran is added dropwise (30 min) having a -78 ⁰ C solution of 0.196 mol of lithium diisopropylamide (from 27.4 ml, 0.196 Mol of diisopropylamine and 85 ml (0.187 mol) of 2.2M n-butyl-lithium in hexane) in 125 ml of tetrahydrofuran. The reaction mixture is kept for a further 30 hours

207 79 9

and then 38 ml (0.383 mol) of 4-bromo-1-butene are added and the reaction mixture is allowed to warm to room temperature, stirred for 1 1/2 hours, and passed through Quenched addition of 5 ml (0.277 mol) of water Most of the solvent is removed under reduced pressure and the residue diluted Tsird with 1 liter of ice water and 500 ml of ether The ethereal extract is washed with two 300 ml portions of water dried, dried over magnesium sulphate and evaporated The distillation of the crude oil gives 10.1 g (29 %) of the title product · b.p .: 83 ^° C. (0.02 Torr).

PMR: J ^ i ₁ 1.34 (t, J = 7 Hz, methyl), 1.3-2.6 (m), 3.86 (q, J ³ = 7 Hz, methylene), 4.75 - 5.2 and 5.45 - 6.2 (m, terminal olefin) and 5.26 (s, vinyl H).

Similarly, the following compounds are prepared from appropriate 3-alkoxy-2-cycloalkene-1-ones and suitable iodides, Rp ¹ J or sromides Rp ¹ Br.

ο _β ,

S R R ₂

1 CH ₃ CH ₃

1 C ₂ H ₅

1 C

1 C ₂ H ₅ Vn-O ₆ H ₁₃

1 O₂H₅ OH₂ Oh ^

1 CH ₃ (CH ₂ ) ₃ CH = CH ₂

R ⁰

(CH ₂ J ₄ CH = CH ₂ CH ₂ CH = CH-CH ₃ (CHg) ₂ CH = CH-CH ₂ CH ₃ CH ₂ C ₆ H ₅ (CH ₂ ) ₄ C ₆ H ₅ 2 1-C ₄ H ₉ nC ₃ H ₇

* 4 9 613

2 i-O.Eg CHp-CH = CHp

2 C ₉ H _R (CH ₀ ) ₀ CH = CH ₉

2ί Π TJ ( / TT ^ f TJ

4 y ί. j} ο ο

2 ^C 2 ^H 5 ^CH 2 ^C 6 ^H 5

2 CH ₃ (CH ₂ ) ₂ CH = CH ₂

3 CH ₃ CH ₃

3 CH ₃ nC ₃ H ₇

3 ⁵¹ ^ ₄ ¹¹ S HC ₅ H ₁₁

3 ⁱ ~ ^c ₄ ^H 9! -C ₃ H ₇

3 ¹ ^ A CH ₂ CH = CH ₂

^{3 1} ^ ₄ ¹¹ S CH ₂ C (CH ₃ ) = C (CH ₃ ) CH,

1 C ₂ H ₅ CH ₂ CH = C (CH ₃ ) 2

3 CH ₃ (CHg) ₂ C ₆ H ₅

Pars tell ting Y

4 ~ j (3-butenyl) - 2 ~ c ycl_ohe_xen-jl-on

To an O ⁰ C-containing slurry of 1.06 g (26 mmol) of lithium aluminum hydride in 75 ml of ether was added a solution of 10 g (51 mmol) of 6- (3-butenyl) -3-ethoxy-2-cyclohexen-1-one given in 25 ml of ether. After stirring for 1 h, the reaction mixture was quenched by the addition of 100 mL of 2% hydrochloric acid. The quenched mixture was stirred for 30 minutes and then extracted with 300 mL of ether. The ether extract was washed with 250 mL of saturated sodium hydroxide.

washed with sodium carbonate, dried over magnesium sulphate and evaporated.

Distillation of the crude oil gave 5.98 g (78 %) of the title product. Boiling point: 133 to 136 ^° C. (22 torr).

PMR: ⁰ ^ q ₁ 1.3-2.7 (m), 4.9-5.4 (m, terminal olefin), 5.5-6.2 3 (m, terminal olefin), 6.02 (bd, J = 10Hz, C-2 vinyl H) and 6.91 (bd, J * = 10Hz, C-3 vinyl H).

By means of this procedure, the compounds listed under Representation X are converted to compounds of the following formula in which R ⁰ , R ₂ ¹ and χ are as defined in Representation X. ,

0 i

Presentation Z

2-Benzylo 2: y "4- (1,1-dimethylheptyl) benzaldehyde 2- (3-Benzyloxy-4-bromophenyl) -2-methyloctane (100 g, 0.257 mol) in tetrahydrofuran (500 ml) slowly became magnesium with a mesh size of 70 to 80 (12.3 g, 0.514 mol), added at such a rate that reflux was maintained "After completion of the addition, the reaction mixture was stirred until it had reached room temperature. it was then further down to 0 ⁰ C cooled. dimethylformamide (29.8 ml, 0.385 mol) was added dropwise over the course of 25 minutes to the reaction mixture (reaction temperature <10 ⁰ G) the ₆ ^ eaktionsge-

The reaction mixture was allowed to warm, then stirred at room temperature for 40 minutes. The reaction mixture was quenched by adding to a saturated aqueous solution of cold ammonium chloride (1800 ml) and the product was extracted with ether (1 liter) was washed twice with saturated sodium chloride (1500 ml), dried over magnesium sulfate and evaporated to a quantitative yield of the title compound as an oil, IR (GHCl ₃ ) 1693, 1618 and 1580 cm ^-1 . MS: (m / e) 333 (if * "), 309, 253, 247 and 91" PlOl: & ™ S ^ o, 82 (terminal 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, CHO).

With the aid of this procedure, the 2-benzyloxy-4- (Z-V /) bromobenzenes of the representations P, H, I, 1 and W are converted into the corresponding benzyldehydes of the formula:

Z-W

where Z and V / correspond to the definition in these representations

Claims (1)

GZ 10928 55 Erfindungoanspruchι 1 «Process for the preparation of a compound of the formula; T * Z-iV where R, ^{e is} selected i \ wherein the dashed lines represent an optical double bond at one of the locations in which case FU can not be present; A, when it stands alone, is hydrogen; B, when it is alone, selected from the group consisting of hydroxy # hydroxymethyl and alkanoyloxy of 1 to 5 carbon atoms; A and B / when taken together ¹ , from which oxo, methylene and alkylenedioxy containing 2 to 4 carbon atoms are selected; _R1 is selected from hydrogen, alkanoyloxy of I to 5 carbon atoms, benzyl, '.- P (O) (OH) "and the mono- and Dinatpiua''and KaXiusiealze thereof" and -CO- (CH ₉₎ -N is selected from the group wherein ρ is an integer of 1 to 4; each of R ₅ and R- when used singly / selected from the group consisting of hydrogen and alkyl of 1 to 4 carbon atoms; R and R when taken together with the nitrogen to which they are attached form a 5- or 6-membered heterocyclic ring selected from the piperidino, pyrrolo, pyrrolidino, morpholino and N-alkylpiperazino 1 to 4 carbon atoms in the alkyl group comprising group; R ₂ atoms selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl having 3 to 6 carbon atoms, phenyl and phenylalkyl having 1 to 4 carbon atoms selected in the group comprising Oer alkyl moiety; R ₃ comprising from aer hydrogen and methyl group; Z is selected from the group comprising (a) alkylene of 1 to 13 carbon atoms; (b) -alk-) -O- (alk ") ° wherein each of (alk -) and (alk ₂ ) 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 ajfe 13, each of m and η is O or 1; and IV from the hydrogen, pyridyl, jC / J ~~ w «. is selected comprehensive group in which W ₁ comprising from hydrogen, fluoro and chloro group; characterized in that a compound of the formula: wherein Q is a phenol protecting group, and X is OQ, or Z ~ W, wherein W 2 and the definition given above correspond ^ a Grignard reaction with a compound uer formula: 07 wherein Y is hydrogen or alkoxy having 1 to 4 carbon atoms and R 'is as defined above, provided that at least one of R "and Y is hydrogen and χ 0, 1, 2 or 3, is subjected, and then, if necessary is one or more of the following transformations: (a) to produce a compound in which the AB is CH ₂ ^ ^>< ^, Component / L, * ^st * Performing a Wittig reaction on the product derived from the Grignard reaction; (b) to produce a compound wherein the AB is CH ₂ OH Component -J ^ ---. η is, carrying out hydroboration-oxidation of the compound in which the AB is CH ₂ Component J * v ^; (c) to produce a compound in which the AB Component alkylenedioxy of 2 to 4 carbon atoms, ketalization of the product from the Grignard reaction;
(d) to produce a compound in which R 'is: or • 453- wherein A and B together form a ketal group, ketalization of the product from the Grignard reaction, where R 'is 0 O if O Il or in the presence of a dehydrating agent; (e) to produce a compound where R * is: or Deketalization of a product obtained by step (d); (f) to produce a compound wherein R * is: JU or I Reaction of the product from the Grignard reaction, wherein R ¹ is 0oo or with dichloromethyllithium; (g) to produce a compound in which A aer OH is reducing the product Component H from the Grignard reaction or from step (e) or (f) by reacting with a metal hydride; (h) to produce a compound wherein R 1 is hydrogen and B is hydroxy, catalytic hydrogenation a product from the Grignard reaction wherein R * is: ⁰ O. ß O or <2 (i) is for producing a compound in which R is hydrogen, removal oer protecting group Q; (j) to produce a compound wherein R is alkanoyloxy, esterifying the product of step (g); (k) to produce a compound wherein -R- is other than hydrogen, esterifying the product of either step (h) or (i); and (1) when the starting material used is one in which X is OQ, removing the protecting groups from the product derived from the Grignard reaction, reacting the product with trimethyl orthoforrhiate in a C, ₄ alkanol in the presence of concentrated sulfuric acid, alkylation or aralkylation of the product followed by decalcification by reaction with hydrochloric acid to give a product of formula I wherein Z is -O (alk) u and VY is water. On fabric or phenyl is « 2e method according to item 1, characterized in that a compound is used as starting material is formula IV used, in which Y is hydrogen, and the Grignard reaction carried out at a in the range of "20 to 0 ⁰ C temperature lying .If" 3 ₀ ^{: A} method according to an aer above points, characterized in that the Grignard reaction takes place in the presence of copper (I) iodide "4" method according to item 1, characterized in that a compound is used as starting material aev formula IV , , in which Y is alkoxy of 1 to 4 carbon atoms and the Grignard reaction at between -30 and +10 ° C temperature lying performed 5 _{β The} method according to any one of the preceding points, characterized in that a Wittig reaction for the conversion of the A B component of 0 in CH ₀ X AX is carried out by reacting with methylenetriphenylphosphorane ,, 6 "Process according to item 5, characterized in that the reaction is carried out at a temperature between room temperature and 80 ^° C.", 7e Method according to any one of items 1, 2, 3, 4 or 5 /, characterized in that the ketalization is carried out for Conversion of component AB from 0 into > <Λ Ketal is made by reacting with a glycol having 2 to 4 carbon atoms * Si 'method according to one of the items 1 and 4, characterized in that a product from the Grignard reaction, where R 'is: OOO ö or with an alkylene glycol having 2 to 4 carbon atoms in the presence of a dehydrating agent and a solvent which allows the azeotropic removal of by-produced water to produce a product wherein R 'is or where A and B together form a ketal group "9"? Process according to item 8, characterized in that the dehydrating agent is p-toluenesulphonic acid and the solvent is benzene « 1Oe method according to one of the items 8 and 9, characterized in that the product obtained by reacting with a mild acid to produce a product in which R 'is .0 or deketalised » Hi, method according to an aer points 1 and 4, characterized in that a product in which R 'is O OO or is Dimethylkupferlithium in an inert solvent at a temperature from 0 to -20 ⁰ C temperature to produce a compound in which R ' or ^C * 3 ^c # 3 CH ₃ is implemented « 12 «A method according to any one of items 1, 2, 3, 4, 10 and 11, characterized in that a verb indung, in Oer the A B-component is 0 to an encryption X A bond in which the component H is OH, by conversion put under a sodium borohydride, potassium borohydride TriSEC ", lithium borohydride, and Diisobutylalunviniumhydrid Lithiumaluminiurahydrid selected reducing agent at a · in the range of -70 to? x 30 ^ο lying! temperature is reduced" -ist · - ' 207 7 ⁽ 13 «Method according to item 12, characterized in that sodium borohydride is used as reducing agent at a temperature in the range of -40 to 30 ^° C using methanol, ethanol or water as solvent.« 14e method according to item 12, characterized in that oil is used as reducing agent potassium tri-sec-butylborohydride at a temperature below -50 ⁰ C in dry tetrahydrofuran as a solvent "15 © method according to one of the items 1 to 4 _# characterized in that as starting materials for the Grignard reaction, a compound of the formula: 0HCH and the formula: wherein Z ₁ VV, R ₂ and η defined in point 1 is used accordingly, and that the product of the Grignard reaction the hydrogenation in the presence of a palladium-platinum catalyst is subjected * 16e A method according to any one of claims! 'to 14 , characterized in that it is in'dem at dor protecting group Q starting material is methyl or ethyl, and that the product of any of items 1 to 14 acid with an under Hydrobronisäure, Polyphosphcrsäure, trifluoro "Oodv / asserstoffsäure, Pyridirihydrochlorid and pyridine hydrobromide reacted reagent selected v / ird _e 17 "method according to item 16, characterized in that iss Ausgengsrnaterial Z is - (alk.) - (alk.) -, wherein elk ^, ^a ^ ^{'<2' ra unc} * ⁿ ^ ^{he De} f * ^ri * ^{t *} - ^ ^R correspond ^on item 1, and that it is in the reagent with which the end product -as * - 207 79 9 is reacted to a polyphosphoric acid or trifluoroacetic acid A process according to any one of items 1 to 14, characterized in that the protective group Q in »starting material is benzyl or substituted benzyl, and that the product is one of items 1 to in the presence of a palladium on carbon catalyst is implemented « 19 * A process according to any one of items 1 to 14, characterized in that it is the protecting group Q in the starting material is benzyl or substituted benzyl, and that the product of a oer points 1 is reacted to with Trxfluoressigsäure or n-Butyllithiutn "